Deguelin对头颈部鳞癌细胞凋亡和自噬的影响及其作用机制研究
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摘要
【目的】
第一部分：研究鱼藤素（deguelin）在体内和体外对头颈部鳞状细胞癌（HNSCC）细胞凋亡的影响。
第二部分：探讨热休克蛋白90（Hsp90）在鱼藤素诱导的HNSCC细胞凋亡中所涉及的信号转导通路及其作用机制。
第三部分：分析腺苷酸活化蛋白激酶（AMPK）在鱼藤素诱导HNSCC细胞凋亡和自噬中关键因子及其作用机制。
【方法】
第一部分：选取人喉癌Hep-2细胞、人表皮鳞癌A-253细胞，人舌鳞状细胞癌SCC-9细胞，分别进行细胞培养，采用免疫学、分子生物学等实验技术，进行MTT、免疫荧光、免疫酶标、Western blot实验等检测细胞凋亡，根据处理的不同药物浓度和时间梯度，分析鱼藤素在体外对细胞死亡和凋亡的影响。在此基础上，将鱼藤素和5-FU联合应用，观察其对Hep-2细胞凋亡的影响。建立裸鼠Hep-2异种移植模型，成瘤后给予灌胃鱼藤素处理，用药期间测量鼠重、肿瘤长径和短径，计算肿瘤体积。观察灌胃一定剂量的鱼藤素对小鼠肿瘤的影响。
第二部分：以HNSCC细胞中Akt、Survivin以及Cdk4的表达为重点研究对象，用Western blot实验、IP实验等方法，探讨Hsp90在鱼藤素诱导的Hep-2细胞、A-253细胞、SCC-9细胞等HNSCC细胞凋亡中的调控作用机制。
第三部分：以AMPK为重点研究对象，以Western blot实验、IP实验、siRNA实验等方法，探讨AMPK在鱼藤素诱导HNSCC细胞凋亡和自噬中的作用机制。
【结果】
第一部分：鱼藤素可不同程度地促进Hep-2细胞、A-253细胞、SCC-9细胞的凋亡，并且此促凋亡作用是时间浓度依赖性的；鱼藤素通过上调Hep-2细胞caspase-3的活性，同时下调Bcl-xL的表达而促进细胞凋亡；低剂量鱼藤素明显增强5-FU诱导的Hep-2细胞的凋亡；灌胃鱼藤素可缩小Hep-2细胞异种移植裸鼠肿瘤的体积，并提高其存活率。
第二部分：鱼藤素抑制Hep-2细胞的Akt信号通路；Hep-2细胞中，鱼藤素阻断Akt与Hsp90相结合，同时促进Akt与泛素相结合，从而促进细胞凋亡；MG-132可逆转鱼藤素诱导的Hep-2细胞Akt以及Hsp90的下调；鱼藤素抑制Hep-2细胞中Survivin和Cdk4的表达；Hep-2细胞中，鱼藤素阻碍Hsp90与Survivin和Cdk4之间的关联，而又促进泛素与Survivin和Cdk4之间的关联；MG-132可逆转鱼藤素诱导的Hep-2细胞Akt的降解；在A-253细胞和SCC-9细胞中，鱼藤素对Akt、Cdk4和Survivin的表达具有相似的抑制作用。
第三部分：伏马毒素B1抑制鱼藤素诱导的Hep-2细胞中神经酰胺的合成；Hep-2细胞中，联用C6神经酰胺加强鱼藤素诱导的细胞死亡，而联用伏马毒素B1减少鱼藤素诱导的细胞死亡；鱼藤素激活Hep-2细胞中LKB1、AMPK、ACC的磷酸化；AMPKɑ1RNAi抑制鱼藤素诱导的Hep-2细胞AMPK的磷酸化；AMPK的激活促进鱼藤素诱导的Hep-2细胞的死亡；C6神经酰胺增强鱼藤素诱导的Hep-2细胞AMPK的磷酸化；Z-VADfmk和3-MA均能够减少鱼藤素诱导的Hep-2细胞的死亡；鱼藤素诱导Hep-2细胞Ulk的磷酸化以及LC3B的表达；鱼藤素促进Hep-2细胞中Ulk和AMPK之间的相互结合；AMPKɑ1RNAi抑制鱼藤素诱导的Hep-2细胞Ulk的磷酸化以及LC3B的表达。
【结论】
第一部分：鱼藤素能够诱导HNSCC细胞凋亡，其机制可能为增加caspase-3的活性，同时下调Bcl-xL的表达，最终诱导细胞的凋亡；低剂量的鱼藤素即能增强人喉鳞癌细胞株Hep-2细胞对5-FU的敏感性。鱼藤素在人喉鳞癌细胞株Hep-2异种移植模型上有显著的抗肿瘤生长和提高生存率的作用。
第二部分：在HNSCC中，鱼藤素通过阻断Hsp90与Akt相互结合，并促进泛素与Akt相结合，从而诱导Akt的降解，影响细胞凋亡。HNSCC细胞中，鱼藤素通过阻断Hsp90与Survivin和Cdk4之间的蛋白结合，同时又促进泛素与Survivin、Cdk4之间相互结合，从而诱导Survivin和Cdk4的降解，影响细胞凋亡。
第三部分：鱼藤素诱导人喉鳞癌细胞株Hep-2细胞中神经酰胺的合成增加，从而进一步激活LKB1-AMPK-ACC的磷酸化，最终增加鱼藤素诱导的Hep-2细胞凋亡。鱼藤素诱导Hep-2细胞AMPK的磷酸化，并进一步激活AMPK/Ulk1依赖的自噬途径，上调LC3B的表达，最终增加鱼藤素诱导的Hep-2细胞自噬。
【Objective】
Part Ⅰ: To analysis the anti-tumor ability of deguelin in vivo and in vitro.
Part Ⅱ: To study the mechanism of heat shock protein (Hsp)90in deguelininduced head and neck squamous cell carcinoma (HNSCC) cell apoptosis.
Part Ⅲ: To investigate mechanism of adenosine monophosphate-activated proteinkinase (AMPK) in deguelin induced HNSCC cell apoptosis and autophagy.
【Methods】
Part Ⅰ: Cell culture of HNSCC cell line Hep-2cells, human epidermalsquamous carcinoma cell line A-253cells, the human tongue squamous cellcarcinoma cell line SCC-9cells, immunology, molecular biology, pathology andother advanced technologies, such as nude mice Hep-2xenograft model to establishthe method of in vivo and in vitro studies of the cell culture, MTT, siRNAtechnology, immunoblotting, and immunofluorescence.
Part Ⅱ: Cell culture of HNSCC cell line Hep-2cells, human epidermalsquamous carcinoma cell line A-253cells, the human tongue squamous cellcarcinoma cell line SCC-9cells, focus on Western blot test, IP experiments of Akt,Survivin and Cdk4.
Part Ⅲ: Cell culture of HNSCC cell line Hep-2cells, MTT, siRNA technology,immunoblotting, immunofluorescence, Western blot experiments, IP experiments, and siRNA experiments.
【Results】
Part Ⅰ: Deguelin promote human laryngeal carcinoma cell line Hep-2cell deathand apoptosis; deguelin promote human epidermal squamous carcinoma cell lineA-253cells, the human tongue squamous cell carcinoma cell line SCC-9cell death;deguelin increased apoptosis by upregulating the Hep-2cells caspase-3activity,while down the expression of BCL-XL; low dose of deguelin markedly enhanced5-FU-induced death of Hep-2cells; low doses of deguelin significantly promote the5-FU-induced apoptosis of Hep-2cells; deguelin reduce the volume of Hep-2cellsxenograft tumors in nude mice, and to improve the survival rate of mice.
Part Ⅱ: Deguelin inhibit Akt signaling pathway in human laryngeal squamouscarcinoma cell line Hep-2cells; deguelin block Akt and Hsp90combined, whilepromoting Akt and ubiquitination combined in Hep-2cells; MG-132reversed the thedeguelin induced Akt and Hsp90downregulation in Hep-2cells; deguelin inhibit theexpression of Survivin and Cdk4in Hep-2cells; in Hep-2cells, deguelin block Hsp90and Survivin and Cdk4inter-related, and promotion of the association betweenubiquitin Survivin and Cdk4; MG-132reversed deguelin induced Akt degradation inHep-2cells; deguelin has a similar inhibitory effect on Akt, Cdk4, and Survivinexpression in human epidermal squamous carcinoma cell line A-253cells andhuman tongue scales-cell carcinoma cell line SCC-9cells.
Part Ⅲ: Fumonisin B1inhibit deguelin induced ceramide synthesis in laryngealsquamous cell carcinoma cell line Hep-2cells; in Hep-2cells, associated with C6ceramide strengthen deguelin induced cell death and apoptosis, but fumonisins B1reduced deguelin induced cell death and apoptosis; deguelin activation LKB1,AMPK, ACC phosphorylation in Hep-2cells; AMPKɑ1RNAi inhibit deguelin induced AMPK phosphorylation in Hep-2cells; AMPK activation enhance deguelininduced Hep-2cell death; C6ceramide enhanced deguelin induced AMPKphosphorylation in Hep-2cells; Z-VADfmk and3-MA reduce deguelin inducedHep-2cells death; deguelin induce phosphorylation of Ulk and LC3B expression inHep-2cells; deguelin promote combination between Ulk and AMPK with each other;AMPK ɑ1RNAi suppress deguelin induced Ulk phosphorylation and LC3Bexpression in Hep-2cells.
【Conclusions】
Part Ⅰ: Deguelin induce HNSCC cell death and apoptosis, the mechanism maybe to increase the activity of caspase-3, at the same time decrease the expression ofBcl-xL, eventually induce laryngeal squamous cell carcinoma cell line Hep-2cellapoptosis; low dose of deguelin can enhance the sensitivity to5-FU of Hep-2cells.Deguelin show significant anti-tumor effects in xenograft models of Hep-2cells.
Part Ⅱ: Deguelin induce the degradation of Akt by blocking Hsp90and Aktbond to each other, and promoting the combination of ubiquitin and Akt, therebyenhance apoptosis in HNSCC cells. In HNSCC cells, deguelin block combination ofHsp90with Survivin and Cdk4, while promoting the ubiquitination bond withSurvivin and Cdk4, thereby inducing degradation of Survivin and Cdk4, increaseapoptosis.
Part Ⅲ: Deguelin induced ceramide synthesis in laryngeal squamous cellcarcinoma cell line Hep-2cells, thereby further activate the LKB1-AMPK-ACCphosphorylation, and ultimately increase deguelin induced cell death and apoptosis.Deguelin induce AMPK phosphorylation and further activation of AMPK/Ulk1dependent autophagy pathway, and increase LC3B expression, ultimately enhancedeguelin induced Hep-2cells death and autophagy.
第一部分：研究鱼藤素（deguelin）在体内和体外对头颈部鳞状细胞癌（HNSCC）细胞凋亡的影响。
第二部分：探讨热休克蛋白90（Hsp90）在鱼藤素诱导的HNSCC细胞凋亡中所涉及的信号转导通路及其作用机制。
第三部分：分析腺苷酸活化蛋白激酶（AMPK）在鱼藤素诱导HNSCC细胞凋亡和自噬中关键因子及其作用机制。
【方法】
第一部分：选取人喉癌Hep-2细胞、人表皮鳞癌A-253细胞，人舌鳞状细胞癌SCC-9细胞，分别进行细胞培养，采用免疫学、分子生物学等实验技术，进行MTT、免疫荧光、免疫酶标、Western blot实验等检测细胞凋亡，根据处理的不同药物浓度和时间梯度，分析鱼藤素在体外对细胞死亡和凋亡的影响。在此基础上，将鱼藤素和5-FU联合应用，观察其对Hep-2细胞凋亡的影响。建立裸鼠Hep-2异种移植模型，成瘤后给予灌胃鱼藤素处理，用药期间测量鼠重、肿瘤长径和短径，计算肿瘤体积。观察灌胃一定剂量的鱼藤素对小鼠肿瘤的影响。
第二部分：以HNSCC细胞中Akt、Survivin以及Cdk4的表达为重点研究对象，用Western blot实验、IP实验等方法，探讨Hsp90在鱼藤素诱导的Hep-2细胞、A-253细胞、SCC-9细胞等HNSCC细胞凋亡中的调控作用机制。
第三部分：以AMPK为重点研究对象，以Western blot实验、IP实验、siRNA实验等方法，探讨AMPK在鱼藤素诱导HNSCC细胞凋亡和自噬中的作用机制。
【结果】
第一部分：鱼藤素可不同程度地促进Hep-2细胞、A-253细胞、SCC-9细胞的凋亡，并且此促凋亡作用是时间浓度依赖性的；鱼藤素通过上调Hep-2细胞caspase-3的活性，同时下调Bcl-xL的表达而促进细胞凋亡；低剂量鱼藤素明显增强5-FU诱导的Hep-2细胞的凋亡；灌胃鱼藤素可缩小Hep-2细胞异种移植裸鼠肿瘤的体积，并提高其存活率。
第二部分：鱼藤素抑制Hep-2细胞的Akt信号通路；Hep-2细胞中，鱼藤素阻断Akt与Hsp90相结合，同时促进Akt与泛素相结合，从而促进细胞凋亡；MG-132可逆转鱼藤素诱导的Hep-2细胞Akt以及Hsp90的下调；鱼藤素抑制Hep-2细胞中Survivin和Cdk4的表达；Hep-2细胞中，鱼藤素阻碍Hsp90与Survivin和Cdk4之间的关联，而又促进泛素与Survivin和Cdk4之间的关联；MG-132可逆转鱼藤素诱导的Hep-2细胞Akt的降解；在A-253细胞和SCC-9细胞中，鱼藤素对Akt、Cdk4和Survivin的表达具有相似的抑制作用。
第三部分：伏马毒素B1抑制鱼藤素诱导的Hep-2细胞中神经酰胺的合成；Hep-2细胞中，联用C6神经酰胺加强鱼藤素诱导的细胞死亡，而联用伏马毒素B1减少鱼藤素诱导的细胞死亡；鱼藤素激活Hep-2细胞中LKB1、AMPK、ACC的磷酸化；AMPKɑ1RNAi抑制鱼藤素诱导的Hep-2细胞AMPK的磷酸化；AMPK的激活促进鱼藤素诱导的Hep-2细胞的死亡；C6神经酰胺增强鱼藤素诱导的Hep-2细胞AMPK的磷酸化；Z-VADfmk和3-MA均能够减少鱼藤素诱导的Hep-2细胞的死亡；鱼藤素诱导Hep-2细胞Ulk的磷酸化以及LC3B的表达；鱼藤素促进Hep-2细胞中Ulk和AMPK之间的相互结合；AMPKɑ1RNAi抑制鱼藤素诱导的Hep-2细胞Ulk的磷酸化以及LC3B的表达。
【结论】
第一部分：鱼藤素能够诱导HNSCC细胞凋亡，其机制可能为增加caspase-3的活性，同时下调Bcl-xL的表达，最终诱导细胞的凋亡；低剂量的鱼藤素即能增强人喉鳞癌细胞株Hep-2细胞对5-FU的敏感性。鱼藤素在人喉鳞癌细胞株Hep-2异种移植模型上有显著的抗肿瘤生长和提高生存率的作用。
第二部分：在HNSCC中，鱼藤素通过阻断Hsp90与Akt相互结合，并促进泛素与Akt相结合，从而诱导Akt的降解，影响细胞凋亡。HNSCC细胞中，鱼藤素通过阻断Hsp90与Survivin和Cdk4之间的蛋白结合，同时又促进泛素与Survivin、Cdk4之间相互结合，从而诱导Survivin和Cdk4的降解，影响细胞凋亡。
第三部分：鱼藤素诱导人喉鳞癌细胞株Hep-2细胞中神经酰胺的合成增加，从而进一步激活LKB1-AMPK-ACC的磷酸化，最终增加鱼藤素诱导的Hep-2细胞凋亡。鱼藤素诱导Hep-2细胞AMPK的磷酸化，并进一步激活AMPK/Ulk1依赖的自噬途径，上调LC3B的表达，最终增加鱼藤素诱导的Hep-2细胞自噬。
【Objective】
Part Ⅰ: To analysis the anti-tumor ability of deguelin in vivo and in vitro.
Part Ⅱ: To study the mechanism of heat shock protein (Hsp)90in deguelininduced head and neck squamous cell carcinoma (HNSCC) cell apoptosis.
Part Ⅲ: To investigate mechanism of adenosine monophosphate-activated proteinkinase (AMPK) in deguelin induced HNSCC cell apoptosis and autophagy.
【Methods】
Part Ⅰ: Cell culture of HNSCC cell line Hep-2cells, human epidermalsquamous carcinoma cell line A-253cells, the human tongue squamous cellcarcinoma cell line SCC-9cells, immunology, molecular biology, pathology andother advanced technologies, such as nude mice Hep-2xenograft model to establishthe method of in vivo and in vitro studies of the cell culture, MTT, siRNAtechnology, immunoblotting, and immunofluorescence.
Part Ⅱ: Cell culture of HNSCC cell line Hep-2cells, human epidermalsquamous carcinoma cell line A-253cells, the human tongue squamous cellcarcinoma cell line SCC-9cells, focus on Western blot test, IP experiments of Akt,Survivin and Cdk4.
Part Ⅲ: Cell culture of HNSCC cell line Hep-2cells, MTT, siRNA technology,immunoblotting, immunofluorescence, Western blot experiments, IP experiments, and siRNA experiments.
【Results】
Part Ⅰ: Deguelin promote human laryngeal carcinoma cell line Hep-2cell deathand apoptosis; deguelin promote human epidermal squamous carcinoma cell lineA-253cells, the human tongue squamous cell carcinoma cell line SCC-9cell death;deguelin increased apoptosis by upregulating the Hep-2cells caspase-3activity,while down the expression of BCL-XL; low dose of deguelin markedly enhanced5-FU-induced death of Hep-2cells; low doses of deguelin significantly promote the5-FU-induced apoptosis of Hep-2cells; deguelin reduce the volume of Hep-2cellsxenograft tumors in nude mice, and to improve the survival rate of mice.
Part Ⅱ: Deguelin inhibit Akt signaling pathway in human laryngeal squamouscarcinoma cell line Hep-2cells; deguelin block Akt and Hsp90combined, whilepromoting Akt and ubiquitination combined in Hep-2cells; MG-132reversed the thedeguelin induced Akt and Hsp90downregulation in Hep-2cells; deguelin inhibit theexpression of Survivin and Cdk4in Hep-2cells; in Hep-2cells, deguelin block Hsp90and Survivin and Cdk4inter-related, and promotion of the association betweenubiquitin Survivin and Cdk4; MG-132reversed deguelin induced Akt degradation inHep-2cells; deguelin has a similar inhibitory effect on Akt, Cdk4, and Survivinexpression in human epidermal squamous carcinoma cell line A-253cells andhuman tongue scales-cell carcinoma cell line SCC-9cells.
Part Ⅲ: Fumonisin B1inhibit deguelin induced ceramide synthesis in laryngealsquamous cell carcinoma cell line Hep-2cells; in Hep-2cells, associated with C6ceramide strengthen deguelin induced cell death and apoptosis, but fumonisins B1reduced deguelin induced cell death and apoptosis; deguelin activation LKB1,AMPK, ACC phosphorylation in Hep-2cells; AMPKɑ1RNAi inhibit deguelin induced AMPK phosphorylation in Hep-2cells; AMPK activation enhance deguelininduced Hep-2cell death; C6ceramide enhanced deguelin induced AMPKphosphorylation in Hep-2cells; Z-VADfmk and3-MA reduce deguelin inducedHep-2cells death; deguelin induce phosphorylation of Ulk and LC3B expression inHep-2cells; deguelin promote combination between Ulk and AMPK with each other;AMPK ɑ1RNAi suppress deguelin induced Ulk phosphorylation and LC3Bexpression in Hep-2cells.
【Conclusions】
Part Ⅰ: Deguelin induce HNSCC cell death and apoptosis, the mechanism maybe to increase the activity of caspase-3, at the same time decrease the expression ofBcl-xL, eventually induce laryngeal squamous cell carcinoma cell line Hep-2cellapoptosis; low dose of deguelin can enhance the sensitivity to5-FU of Hep-2cells.Deguelin show significant anti-tumor effects in xenograft models of Hep-2cells.
Part Ⅱ: Deguelin induce the degradation of Akt by blocking Hsp90and Aktbond to each other, and promoting the combination of ubiquitin and Akt, therebyenhance apoptosis in HNSCC cells. In HNSCC cells, deguelin block combination ofHsp90with Survivin and Cdk4, while promoting the ubiquitination bond withSurvivin and Cdk4, thereby inducing degradation of Survivin and Cdk4, increaseapoptosis.
Part Ⅲ: Deguelin induced ceramide synthesis in laryngeal squamous cellcarcinoma cell line Hep-2cells, thereby further activate the LKB1-AMPK-ACCphosphorylation, and ultimately increase deguelin induced cell death and apoptosis.Deguelin induce AMPK phosphorylation and further activation of AMPK/Ulk1dependent autophagy pathway, and increase LC3B expression, ultimately enhancedeguelin induced Hep-2cells death and autophagy.
引文
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18. Wang, C. and J. Chen, Phosphorylation and hsp90binding mediate heatshock stabilization of p53. J Biol Chem,2003.278(3): p.2066-71.
19. Sato, S., N. Fujita, and T. Tsuruo, Modulation of Akt kinase activity bybinding to Hsp90. Proc Natl Acad Sci U S A,2000.97(20): p.10832-7.
20. Fortugno, P., et al., Regulation of survivin function by Hsp90. Proc Natl AcadSci U S A,2003.100(24): p.13791-6.
21. Vaughan, C.K., et al., Structure of an Hsp90-Cdc37-Cdk4complex. Mol Cell,2006.23(5): p.697-707.
22. Stepanova, L., et al., Mammalian p50Cdc37is a protein kinase-targetingsubunit of Hsp90that binds and stabilizes Cdk4. Genes Dev,1996.10(12): p.1491-502.
23. Kabakov, A.E., V.A. Kudryavtsev, and V.L. Gabai, Hsp90inhibitors aspromising agents for radiotherapy. J Mol Med (Berl),2010.88(3): p.241-7.
24. Oh, S.H., et al., Structural basis for depletion of heat shock protein90clientproteins by deguelin. J Natl Cancer Inst,2007.99(12): p.949-61.
25. Vivanco, I. and C.L. Sawyers, The phosphatidylinositol3-Kinase AKTpathway in human cancer. Nat Rev Cancer,2002.2(7): p.489-501.
26. Dou, H.J. and J.P. Hu,[Progress of study on survivin in diffuse large B-celllymphoma--review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2008.16(6): p.1487-90.
27. Ji, C., et al., Exogenous cell-permeable C6ceramide sensitizes multiplecancer cell lines to Doxorubicin-induced apoptosis by promoting AMPKactivation and mTORC1inhibition. Oncogene,2010.29(50): p.6557-68.
28. Gruzman, A., G. Babai, and S. Sasson, Adenosine Monophosphate-ActivatedProtein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Reviewon Metabolic, Pharmacological and Chemical Considerations. Rev DiabetStud,2009.6(1): p.13-36.
29. Lage, R., et al., AMPK: a metabolic gauge regulating whole-body energyhomeostasis. Trends Mol Med,2008.14(12): p.539-49.
30. Rattan, R., et al.,5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosideinhibits cancer cell proliferation in vitro and in vivo via AMP-activatedprotein kinase. J Biol Chem,2005.280(47): p.39582-93.
31. Viollet, B., et al., AMPK inhibition in health and disease. Crit Rev BiochemMol Biol.45(4): p.276-95.
32. Zhou, G., I.K. Sebhat, and B.B. Zhang, AMPK activators--potentialtherapeutics for metabolic and other diseases. Acta Physiol (Oxf),2009.196(1): p.175-90.
33. Shaw, R.J., LKB1and AMP-activated protein kinase control of mTORsignalling and growth. Acta Physiol (Oxf),2009.196(1): p.65-80.
34. Kaushik, S. and A.M. Cuervo, Chaperone-mediated autophagy: a unique wayto enter the lysosome world. Trends Cell Biol,2012.22(8): p.407-17.
35. Huang, W.P. and D.J. Klionsky, Autophagy in yeast: a review of themolecular machinery. Cell Struct Funct,2002.27(6): p.409-20.
36. Vicencio, J.M., et al., Senescence, apoptosis or autophagy? When a damagedcell must decide its path--a mini-review. Gerontology,2008.54(2): p.92-9.
37. Tsuchihara, K., S. Fujii, and H. Esumi, Autophagy and cancer: dynamism ofthe metabolism of tumor cells and tissues. Cancer Lett,2009.278(2): p.130-8.
38. Lorin, S., P. Codogno, and M. Djavaheri-Mergny,[Autophagy: a new conceptin cancer research]. Bull Cancer,2008.95(1): p.43-50.
39. Reynolds, C.P., B.J. Maurer, and R.N. Kolesnick, Ceramide synthesis andmetabolism as a target for cancer therapy. Cancer Lett,2004.206(2): p.169-80.
40. Zhu, Q.Y., et al., C6-ceramide synergistically potentiates the anti-tumoreffects of histone deacetylase inhibitors via AKT dephosphorylation andalpha-tubulin hyperacetylation both in vitro and in vivo. Cell Death Dis,
2011.2: p. e117.
41. Ji, C., et al., Increasing ceramides sensitizes genistein-induced melanoma cellapoptosis and growth inhibition. Biochem Biophys Res Commun,2012.421(3): p.462-7.
42. Ji, C., et al., Perifosine sensitizes UVB-induced apoptosis in skin cells: newimplication of skin cancer prevention? Cell Signal,2012.24(9): p.1781-9.
43. Bose, R., et al., Ceramide synthase mediates daunorubicin-induced apoptosis:an alternative mechanism for generating death signals. Cell,1995.82(3): p.405-14.
44. Kolesnick, R.N. and M. Kronke, Regulation of ceramide production andapoptosis. Annu Rev Physiol,1998.60: p.643-65.
45. Merrill, A.H., Jr., et al., Fumonisin B1inhibits sphingosine (sphinganine)N-acyltransferase and de novo sphingolipid biosynthesis in cultured neuronsin situ. J Biol Chem,1993.268(36): p.27299-306.
46. Charles, A.G., et al., Taxol-induced ceramide generation and apoptosis inhuman breast cancer cells. Cancer Chemother Pharmacol,2001.47(5): p.444-50.
47. Lee, J.H., et al., Exchange-coupled magnetic nanoparticles for efficient heatinduction. Nat Nanotechnol,2011.6(7): p.418-22.
48. Lee, J.W., et al., The association of AMPK with ULK1regulates autophagy.PLoS One,2011.5(11): p. e15394.
[1] Yan Y, Wang Y, Tan Q, et al. Efficacy of deguelin and silibinin onbenzo(a)pyrene-induced lung tumorigenesis in A/J mice. In Neoplasia.2005;1053-1057.
[2] Memmott RM, Dennis PA. The role of the Akt/mTOR pathway in tobaccocarcinogen-induced lung tumorigenesis. Clin Cancer Res2010;16:4-10.
[3] Lee HY, Oh SH, Woo JK, et al. Chemopreventive effects of deguelin, a novelAkt inhibitor, on tobacco-induced lung tumorigenesis. J Natl Cancer Inst2005;97:1695-1699.
[4] Jin Q, Feng L, Behrens C, et al. Implication of AMP-activated protein kinaseand Akt-regulated survivin in lung cancer chemopreventive activities ofdeguelin. Cancer Res2007;67:11630-11639.
[5] Murillo G, Salti GI, Kosmeder JW2nd, et al. Deguelin inhibits the growth ofcolon cancer cells through the induction of apoptosis and cell cycle arrest. Eur JCancer2002;38:2446-2454.
[6] Kang HW, Kim JM, Cha MY, et al. Deguelin, an Akt inhibitor, down-regulatesNF-kappaB signaling and induces apoptosis in colon cancer cells and inhibitstumor growth in mice. Dig Dis Sci2012;57:2873-2882.
[7] Peng XH, Karna P, O'Regan RM, et al. Down-regulation of inhibitor ofapoptosis proteins by deguelin selectively induces apoptosis in breast cancercells. Mol Pharmacol2007;71:101-111.
[8]初钊辉,梁晓华,周鑫莉,等.鱼藤素对乳腺癌细胞株MCF-7增殖和凋亡及PI3K/Akt信号通路的影响.中西医结合学报2011；9:533-538.
[9] Chen Y, Wu Q, Cui GH, et al. Deguelin blocks cells survival signal pathwaysand induces apoptosis of HL-60cells in vitro. Int J Hematol2009;89:618-623.
[10]吴宏禧，游志鹏．HIF-1调节机制在糖尿病视网膜血管及神经病变中的研究进展.国际眼科杂志2009;9:1937-1940．
[11]Ito S, Oyake T, Murai K, et al. Deguelin suppresses cell proliferation via theinhibition of survivin expression and STAT3phosphorylation in HTLV-1-transformed T cells. Leuk Res2010;34:352-357.
[12]Gills JJ, Kosmeder J2nd, Moon RC et al. Effect of deguelin on UVB-inducedskin carcinogenesis. J Chemother2005;17:297-301.
[13]Boreddy SR, Srivastava SK. Deguelin suppresses pancreatic tumor growth andmetastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopicmodel. Oncogene2012Sep17. doi:10.1038/onc.2012.413.[Epub ahead ofprint]
[14]Lee H, Lee JH, Jung KH, et al. Deguelin promotes apoptosis and inhibitsangiogenesis of gastric cancer. Oncol Rep2010;24:957-963.
[15]Thamilselvan V, Menon M, Thamilselvan S. Anticancer efficacy of deguelin inhuman prostate cancer cells targeting glycogen synthase kinase-3beta/beta-catenin pathway. Int J Cancer2011;129:2916-2927.
[16]Dell'Eva R, Ambrosini C, Minghelli S, et al. The Akt inhibitor deguelin, is anangiopreventive agent also acting on the NF-kappaB pathway. Carcinogenesis2007;28:404-413.
[17]Lee JH, Lee DH, Lee HS, et al. Deguelin inhibits human hepatocellularcarcinoma by antiangiogenesis and apoptosis. Oncol Rep2008;20:129-134.
[18]Kim JH, Kim JH, Yu YS, et al. Deguelin inhibits retinal neovascularization bydown-regulation of HIF-1alpha in oxygen-induced retinopathy. J Cell Mol Med2008;12:2407-2415.
[19]Kim JH, Kim JH, Yu YS, et al. Antiangiogenic effect of deguelin on choroidalneovascularization. J Pharmacol Exp Ther2008;324:643-647.
[20]Oh SH, Woo JK, Jin Q, et al. Identification of novel antiangiogenic anticanceractivities of deguelin targeting hypoxia-inducible factor-1alpha. Int J Cancer2008;122:5-14.
[21]Paulus P, Ockelmann P, Tacke S, et al. Deguelin attenuates reperfusion injuryand improves outcome after orthotopic lung transplantation in the rat. PLoS One2012;7: e39265.
[22]Oh SH, Woo JK, Yazici YD, et al. Structural basis for depletion of heat shockprotein90client proteins by deguelin. J Natl Cancer Inst2007;99:949-961.
[23]Chang DJ, An H, Kim KS, et al. Design, synthesis, and biological evaluation ofnovel deguelin-based heat shock protein90(HSP90) inhibitors targetingproliferation and angiogenesis. J Med Chem2012;55:10863-10884.
[24]Garcia J, Barluenga S, Gorska K, et al. Synthesis of deguelin-biotin conjugatesand investigation into deguelin's interactions. Bioorg Med Chem2012;20:672-680.
[25]Hu J, Ye H, Fu A, et al. Deguelin--an inhibitor to tumor lymphangiogenesis andlymphatic metastasis by downregulation of vascular endothelial cell growthfactor-D in lung tumor model. Int J Cancer2010;127:2455-2466.
[26]Bortul R, Tazzari PL, Billi AM, et al. Deguelin, A PI3K/AKT inhibitor, enhanceschemosensitivity of leukaemia cells with an active PI3K/AKT pathway. Br JHaematol2005;129:677-686.
[27]Yi T, Li H, Wang X, et al. Enhancement radiosensitization of breast cancer cellsby deguelin. Cancer Biother Radiopharm2008;23:355-362.
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[29]Geeraerts B, Vanhoecke B, Vanden Berghe W, et al. Deguelin inhibits expressionof IkappaBalpha protein and induces apoptosis of B-CLL cells in vitro.Leukemia2007;21:1610-1618.
[30]Li R, Chen Y, Shu WX, et al. Involvement of SRC-3in deguelin-inducedapoptosis in Jurkat cells. Int J Hematol2009;89:628-635.
[31]Chen WH, Chen Y, Cui GH. Deguelin inhibits expression of IkappaBalphaprotein in Raji and U937cells. Acta Pharmacol Sin2006;27:485-490.
[32]Wu Q, Chen Y, Liu H, et al. Anti-cancer effects of deguelin on human leukemiaK562and K562/ADM cells In Vitro. J Huazhong Univ Sci Technolog Med Sci2007;27:149-152.
[33]刘红利,陈燕,崔国惠,等.鱼藤素对淋巴瘤Daudi细胞株细胞增殖细胞凋亡的影响及其机制.中华肿瘤杂志2007;29:176-180.
[34]Liu HL, Chen Y, Cui GH, et al. Regulating expressions of cyclin D1, pRb, andanti-cancer effects of deguelin on human Burkitt's lymphoma Daudi cells invitro. Acta Pharmacol Sin2005;26:873-880.
[35]Shu W, Chen Y, Wu Q, et al. Deguelin represses both the expression ofnucleophosmin and some nucleoporins: Nup88and Nup214in Jurkat cells. BiolPharm Bull2008;31:27-32.
[36]Matsuda H, Yoshida K, Miyagawa K, et al. Rotenoids and flavonoids withanti-invasion of HT1080, anti-proliferation of U937, anddifferentiation-inducing activity in HL-60from Erycibe expansa. Bioorg MedChem2007;15:1539-1546.
[37]陈燕,刘红利,崔国惠,等.鱼藤素对U937细胞细胞周期及核孔蛋白Nup98和Nup88的调控作用.中华血液学杂志2007;28:115-118.
[38]吴秋玲,陈燕,陈卫华,等.鱼藤素对K562细胞nup98表达的影响.中国实验血液学杂志2007;15:25-28.
[39]Chun KH, Kosmeder JW2nd, Sun S, et al. Effects of deguelin on thephosphatidylinositol3-kinase/Akt pathway and apoptosis in premalignanthuman bronchial epithelial cells. J Natl Cancer Inst2003;95:291-302.
[40]Rodenberg JM, Brown PH. A novel look into estrogen receptor-negative breastcancer prevention with the natural, multifunctional signal transduction inhibitordeguelin. Cancer Prev Res (Phila)2009;2:915-918.
[41]Murillo G, Peng X, Torres KE, et al. Deguelin inhibits growth of breast cancercells by modulating the expression of key members of the Wnt signalingpathway. Cancer Prev Res (Phila)2009;2:942-950.
[42]Hail N Jr, Lotan R. Apoptosis induction by the natural product cancerchemopreventive agent deguelin is mediated through the inhibition ofmitochondrial bioenergetics. Apoptosis2004;9:437-447.
[43]杜佳,邓华瑜,姜蓉,等.鱼藤素对乳腺癌细胞MDA-MB-231线粒体通透性转换孔的作用.第二军医大学学报2010;31:102-105.
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[46]Lee HY. Molecular mechanisms of deguelin-induced apoptosis in transformedhuman bronchial epithelial cells. Biochem Pharmacol2004;68:1119-1124.
[47]Thakor NV, Zhu YS, Pan KY. Ventricular tachycardia and fibrillation detectionby a sequential hypothesis testing algorithm. IEEE Trans Biomed Eng1990;37:837-843.
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2. Swoboda, H. and D.M. Denk, Diagnosis and therapy of laryngeal carcinoma.Radiologe,1998.38(2): p.83-92.
3. Lee, H.Y., et al., Chemopreventive effects of deguelin, a novel Akt inhibitor,on tobacco-induced lung tumorigenesis. J Natl Cancer Inst,2005.97(22): p.1695-9.
4. Jemal, A., et al., Cancer statistics,2003. CA Cancer J Clin,2003.53(1): p.5-26.
5. LoTempio, M.M., et al., Curcumin suppresses growth of head and necksquamous cell carcinoma. Clin Cancer Res,2005.11(19Pt1): p.6994-7002.
6. Stell, P.M., Time to recurrence of squamous cell carcinoma of the head andneck. Head Neck,1991.13(4): p.277-81.
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8. Brockstein, B., et al., Patterns of failure, prognostic factors and survival inlocoregionally advanced head and neck cancer treated with concomitantchemoradiotherapy: a9-year,337-patient, multi-institutional experience.Ann Oncol,2004.15(8): p.1179-86.
9. Murillo, G., et al., Deguelin suppresses the formation of carcinogen-inducedaberrant crypt foci in the colon of CF-1mice. Int J Cancer,2003.104(1): p.7-11.
10. Udeani, G.O., et al., Cancer chemopreventive activity mediated by deguelin, anaturally occurring rotenoid. Cancer Res,1997.57(16): p.3424-8.
11. Bortul, R., et al., Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivityof leukaemia cells with an active PI3K/AKT pathway. Br J Haematol,2005.129(5): p.677-86.
12. Gerhauser, C., et al., Rotenoids mediate potent cancer chemopreventiveactivity through transcriptional regulation of ornithine decarboxylase. NatMed,1995.1(3): p.260-6.
13. Mollereau, B., Cell death: what can we learn from flies? Editorial for thespecial review issue on Drosophila apoptosis. Apoptosis,2009.14(8): p.929-34.
14. Hector, S. and J.H. Prehn, Apoptosis signaling proteins as prognosticbiomarkers in colorectal cancer: a review. Biochim Biophys Acta,2009.1795(2): p.117-29.
15. Katschinski, D.M., et al., Heat induction of the unphosphorylated form ofhypoxia-inducible factor-1alpha is dependent on heat shock protein-90activity. J Biol Chem,2002.277(11): p.9262-7.
16. Isaacs, J.S., et al., Hsp90regulates a von Hippel Lindau-independenthypoxia-inducible factor-1alpha-degradative pathway. J Biol Chem,2002.277(33): p.29936-44.
17. Peng, Y., et al., Inhibition of MDM2by hsp90contributes to mutant p53stabilization. J Biol Chem,2001.276(44): p.40583-90.
18. Wang, C. and J. Chen, Phosphorylation and hsp90binding mediate heatshock stabilization of p53. J Biol Chem,2003.278(3): p.2066-71.
19. Sato, S., N. Fujita, and T. Tsuruo, Modulation of Akt kinase activity bybinding to Hsp90. Proc Natl Acad Sci U S A,2000.97(20): p.10832-7.
20. Fortugno, P., et al., Regulation of survivin function by Hsp90. Proc Natl AcadSci U S A,2003.100(24): p.13791-6.
21. Vaughan, C.K., et al., Structure of an Hsp90-Cdc37-Cdk4complex. Mol Cell,2006.23(5): p.697-707.
22. Stepanova, L., et al., Mammalian p50Cdc37is a protein kinase-targetingsubunit of Hsp90that binds and stabilizes Cdk4. Genes Dev,1996.10(12): p.1491-502.
23. Kabakov, A.E., V.A. Kudryavtsev, and V.L. Gabai, Hsp90inhibitors aspromising agents for radiotherapy. J Mol Med (Berl),2010.88(3): p.241-7.
24. Oh, S.H., et al., Structural basis for depletion of heat shock protein90clientproteins by deguelin. J Natl Cancer Inst,2007.99(12): p.949-61.
25. Vivanco, I. and C.L. Sawyers, The phosphatidylinositol3-Kinase AKTpathway in human cancer. Nat Rev Cancer,2002.2(7): p.489-501.
26. Dou, H.J. and J.P. Hu,[Progress of study on survivin in diffuse large B-celllymphoma--review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi,2008.16(6): p.1487-90.
27. Ji, C., et al., Exogenous cell-permeable C6ceramide sensitizes multiplecancer cell lines to Doxorubicin-induced apoptosis by promoting AMPKactivation and mTORC1inhibition. Oncogene,2010.29(50): p.6557-68.
28. Gruzman, A., G. Babai, and S. Sasson, Adenosine Monophosphate-ActivatedProtein Kinase (AMPK) as a New Target for Antidiabetic Drugs: A Reviewon Metabolic, Pharmacological and Chemical Considerations. Rev DiabetStud,2009.6(1): p.13-36.
29. Lage, R., et al., AMPK: a metabolic gauge regulating whole-body energyhomeostasis. Trends Mol Med,2008.14(12): p.539-49.
30. Rattan, R., et al.,5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosideinhibits cancer cell proliferation in vitro and in vivo via AMP-activatedprotein kinase. J Biol Chem,2005.280(47): p.39582-93.
31. Viollet, B., et al., AMPK inhibition in health and disease. Crit Rev BiochemMol Biol.45(4): p.276-95.
32. Zhou, G., I.K. Sebhat, and B.B. Zhang, AMPK activators--potentialtherapeutics for metabolic and other diseases. Acta Physiol (Oxf),2009.196(1): p.175-90.
33. Shaw, R.J., LKB1and AMP-activated protein kinase control of mTORsignalling and growth. Acta Physiol (Oxf),2009.196(1): p.65-80.
34. Kaushik, S. and A.M. Cuervo, Chaperone-mediated autophagy: a unique wayto enter the lysosome world. Trends Cell Biol,2012.22(8): p.407-17.
35. Huang, W.P. and D.J. Klionsky, Autophagy in yeast: a review of themolecular machinery. Cell Struct Funct,2002.27(6): p.409-20.
36. Vicencio, J.M., et al., Senescence, apoptosis or autophagy? When a damagedcell must decide its path--a mini-review. Gerontology,2008.54(2): p.92-9.
37. Tsuchihara, K., S. Fujii, and H. Esumi, Autophagy and cancer: dynamism ofthe metabolism of tumor cells and tissues. Cancer Lett,2009.278(2): p.130-8.
38. Lorin, S., P. Codogno, and M. Djavaheri-Mergny,[Autophagy: a new conceptin cancer research]. Bull Cancer,2008.95(1): p.43-50.
39. Reynolds, C.P., B.J. Maurer, and R.N. Kolesnick, Ceramide synthesis andmetabolism as a target for cancer therapy. Cancer Lett,2004.206(2): p.169-80.
40. Zhu, Q.Y., et al., C6-ceramide synergistically potentiates the anti-tumoreffects of histone deacetylase inhibitors via AKT dephosphorylation andalpha-tubulin hyperacetylation both in vitro and in vivo. Cell Death Dis,
2011.2: p. e117.
41. Ji, C., et al., Increasing ceramides sensitizes genistein-induced melanoma cellapoptosis and growth inhibition. Biochem Biophys Res Commun,2012.421(3): p.462-7.
42. Ji, C., et al., Perifosine sensitizes UVB-induced apoptosis in skin cells: newimplication of skin cancer prevention? Cell Signal,2012.24(9): p.1781-9.
43. Bose, R., et al., Ceramide synthase mediates daunorubicin-induced apoptosis:an alternative mechanism for generating death signals. Cell,1995.82(3): p.405-14.
44. Kolesnick, R.N. and M. Kronke, Regulation of ceramide production andapoptosis. Annu Rev Physiol,1998.60: p.643-65.
45. Merrill, A.H., Jr., et al., Fumonisin B1inhibits sphingosine (sphinganine)N-acyltransferase and de novo sphingolipid biosynthesis in cultured neuronsin situ. J Biol Chem,1993.268(36): p.27299-306.
46. Charles, A.G., et al., Taxol-induced ceramide generation and apoptosis inhuman breast cancer cells. Cancer Chemother Pharmacol,2001.47(5): p.444-50.
47. Lee, J.H., et al., Exchange-coupled magnetic nanoparticles for efficient heatinduction. Nat Nanotechnol,2011.6(7): p.418-22.
48. Lee, J.W., et al., The association of AMPK with ULK1regulates autophagy.PLoS One,2011.5(11): p. e15394.
[1] Yan Y, Wang Y, Tan Q, et al. Efficacy of deguelin and silibinin onbenzo(a)pyrene-induced lung tumorigenesis in A/J mice. In Neoplasia.2005;1053-1057.
[2] Memmott RM, Dennis PA. The role of the Akt/mTOR pathway in tobaccocarcinogen-induced lung tumorigenesis. Clin Cancer Res2010;16:4-10.
[3] Lee HY, Oh SH, Woo JK, et al. Chemopreventive effects of deguelin, a novelAkt inhibitor, on tobacco-induced lung tumorigenesis. J Natl Cancer Inst2005;97:1695-1699.
[4] Jin Q, Feng L, Behrens C, et al. Implication of AMP-activated protein kinaseand Akt-regulated survivin in lung cancer chemopreventive activities ofdeguelin. Cancer Res2007;67:11630-11639.
[5] Murillo G, Salti GI, Kosmeder JW2nd, et al. Deguelin inhibits the growth ofcolon cancer cells through the induction of apoptosis and cell cycle arrest. Eur JCancer2002;38:2446-2454.
[6] Kang HW, Kim JM, Cha MY, et al. Deguelin, an Akt inhibitor, down-regulatesNF-kappaB signaling and induces apoptosis in colon cancer cells and inhibitstumor growth in mice. Dig Dis Sci2012;57:2873-2882.
[7] Peng XH, Karna P, O'Regan RM, et al. Down-regulation of inhibitor ofapoptosis proteins by deguelin selectively induces apoptosis in breast cancercells. Mol Pharmacol2007;71:101-111.
[8]初钊辉,梁晓华,周鑫莉,等.鱼藤素对乳腺癌细胞株MCF-7增殖和凋亡及PI3K/Akt信号通路的影响.中西医结合学报2011；9:533-538.
[9] Chen Y, Wu Q, Cui GH, et al. Deguelin blocks cells survival signal pathwaysand induces apoptosis of HL-60cells in vitro. Int J Hematol2009;89:618-623.
[10]吴宏禧，游志鹏．HIF-1调节机制在糖尿病视网膜血管及神经病变中的研究进展.国际眼科杂志2009;9:1937-1940．
[11]Ito S, Oyake T, Murai K, et al. Deguelin suppresses cell proliferation via theinhibition of survivin expression and STAT3phosphorylation in HTLV-1-transformed T cells. Leuk Res2010;34:352-357.
[12]Gills JJ, Kosmeder J2nd, Moon RC et al. Effect of deguelin on UVB-inducedskin carcinogenesis. J Chemother2005;17:297-301.
[13]Boreddy SR, Srivastava SK. Deguelin suppresses pancreatic tumor growth andmetastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopicmodel. Oncogene2012Sep17. doi:10.1038/onc.2012.413.[Epub ahead ofprint]
[14]Lee H, Lee JH, Jung KH, et al. Deguelin promotes apoptosis and inhibitsangiogenesis of gastric cancer. Oncol Rep2010;24:957-963.
[15]Thamilselvan V, Menon M, Thamilselvan S. Anticancer efficacy of deguelin inhuman prostate cancer cells targeting glycogen synthase kinase-3beta/beta-catenin pathway. Int J Cancer2011;129:2916-2927.
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