胰岛素样生长因子I型受体作为肿瘤治疗靶点的研究
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摘要
胰岛素生长因子I型受体(Insulin-like growth factor-Ⅰreceptor, IGF-IR)是细胞表面跨膜酪氨酸激酶受体,在细胞的增殖、分化、凋亡和转移中发挥重要的功能。IGF-IR在很多肿瘤中过表达,包括乳腺癌、肺癌、宫颈癌、肾母细胞瘤等。另外研究发现IGF-IR在正常肝细胞中低表达,而在肝细胞肝癌(Hepatocellular carcinoma, HCC)中高表达。在对HCC进行治疗时,IGF-IR信号的活化是HCC对很多化疗药物产生耐药的重要原因之一。因此,在对HCC进行治疗的过程中,IGF-IR是个潜在的治疗靶点。目前已经开发了很多针对IGF-IR胞内区酪氨酸激酶的小分子抑制剂,但由于IGF-IR胞内区与IR具有很高的同源性,这种小分子抑制剂的应用前景受到挑战。最近开发了许多针对IGF-IR的特异性单克隆抗体,虽然这些抗体针对很多肿瘤细胞做了临床前的研究,但关于抗IGF-IR的单克隆抗体对HCC治疗效果还没有进行全面的研究报道。
本研究通过杂交瘤技术筛选出针对IGF-IR的单克隆抗体4F2,4F2能抑制配体IGF-Ⅰ/Ⅱ与受体IGF-IR的结合,但不能抑制胰岛素与其受体IR的结合；CCK-8检测发现4F2抑制了HCC细胞的增殖,当其与阿霉素联用时抑制效果比单用时更明显；4F2能抑制IGF-IR及作用底物IRS-1的磷酸化,以及抑制IGF-IR下游信号通路分子的活化。在4F2作用肿瘤细胞48小时后引起IGF-IR表达下调；4F2和阿霉素单用时引起细胞发生凋亡,当两者联合使用时增强了细胞的凋亡率,通过对前凋亡分子以及抗凋亡分子表达变化的检测得到进一步证实；体内治疗结果显示,4F2单独使用时,效果不明显,但当其阿霉素联用时增强了阿霉素的抑瘤作用。
在全世界头颈癌(squamous cell carcinomas of the head and neck, SCCHN)是第十种最流行的癌症。尽管在目前的治疗方法有了很大的提高,在过去的10年中5年生存率却依然很低。因此,特别是对于低分化的SCCHN,发现新的、有效的分子靶向治疗方法及其分子作用机制是很重要的治疗途径。
IGF-IR在癌症治疗中是一个新的潜在的靶点。以前也有研究证明在SCCHN中有IGF-IR过表达,而且IGF-IR信号的活化增强了头颈癌细胞的增殖、迁移。但到目前为止,通过IGF-IR的反义寡核苷酸单独或与化疗药对SCCHN进行联合治疗的效果未曾有报道,本研究试图通过下调IGF-IR的表达来观察对IGF-IR通路的抑制能否增强化疗药对SCCHN的敏感性。IGF-IR的硫代磷酸反义寡核苷酸(phosphorothioate antisense oligonucleotides, AS[S]ODN)下调了IGF-IR的表达,抑制TU159和183A细胞增殖,减弱了IGF-IR的磷酸化及其下游信号通路的活化。AS[S]ODN提高了化疗药物对TU159和183A细胞的抑制作用,增强了化疗药阿霉素诱导的细胞凋亡。体内实验发现,AS[S]ODN增强了阿霉素对TU159肿瘤的抑制作用。
IGF-IR is a membrane-bound tyrosine kinase receptor that plays a critical role in tumor cell proliferation, differentiation and apoptosis. The IGF-IR expression was constitutively low in normal hepatocytes and overexpressed in HCC. And what's more, the level of ligand IGF-Ⅱis highly expressed in many human malignancies, including breast cancer, pediatric tumors, colon cancer and HCC. Therefore, IGF-IR is an attractive anti-tumor target for HCC.Because of high homology to insulin receptor, the development of specific small molecule inhibitors of IGF-IR tyrosine kinase activity was challengeable. Recently, many specific neutralizing antibodies for IGF-IR have been researched. Although the effects of anti-tumor about theses antibodies were tested for several cell types, no comprehensive research on the anti-tumorignic impact on HCC cells have been reported to date.
Here, we generated a murine anti-IGF-IR antibody and tested our hypothesis both in vitro and in vivo by treating HCC tumor cells with the 4F2 antibody alone and in combination with the cytotoxic chemotherapeutic drugs. The anti-IGF-IR therapeutic antibody 4F2 blocks IGF-induced IGF-IR signaling and downregulates the expression of IGF-IR in HCC cells. The antitumor effect of treatment with doxorubicin could be enhanced by combining it with the 4F2.
Squamous cell carcinoma of head and neck (HNSCC) is the tenth most common cancer in worldwide. In spite of advances in recent therapies, the 5-year mortality rate of SCCHN patients has not improved in the past few decades. It is important to discover novel and effective molecular-targeted approaches. Previous studies have indicated that IGF-IR is highly expressed in human head and neck cancer and that IGF-IR signaling significantly improves the proliferation, motility, and tumorigenicity of human head and neck cancer cell lines. However, the function of IGF-IR overexpression regarding therapy in human head and neck cancer is still unclear.
In this study, we attempt to investigate whether IGF-IR downregulation results in an enhanced chemosensitive phenotype of head and neck cancer cells. Compared to phosphorothioate sense oligonucleotides (SS[S]ODN), IGF-IR phosphorothioate antisense oligonucleotides (AS[S]ODN) treatment inhibited cancer cell proliferation and attenuated activation of IGF-IR, IRS-1, Erk and Akt. IGF-IR antisense treatment was shown to enhance the sensitivity of SCCHN cell lines to doxorubicin in vitro and in vivo.
本研究通过杂交瘤技术筛选出针对IGF-IR的单克隆抗体4F2,4F2能抑制配体IGF-Ⅰ/Ⅱ与受体IGF-IR的结合,但不能抑制胰岛素与其受体IR的结合；CCK-8检测发现4F2抑制了HCC细胞的增殖,当其与阿霉素联用时抑制效果比单用时更明显；4F2能抑制IGF-IR及作用底物IRS-1的磷酸化,以及抑制IGF-IR下游信号通路分子的活化。在4F2作用肿瘤细胞48小时后引起IGF-IR表达下调；4F2和阿霉素单用时引起细胞发生凋亡,当两者联合使用时增强了细胞的凋亡率,通过对前凋亡分子以及抗凋亡分子表达变化的检测得到进一步证实；体内治疗结果显示,4F2单独使用时,效果不明显,但当其阿霉素联用时增强了阿霉素的抑瘤作用。
在全世界头颈癌(squamous cell carcinomas of the head and neck, SCCHN)是第十种最流行的癌症。尽管在目前的治疗方法有了很大的提高,在过去的10年中5年生存率却依然很低。因此,特别是对于低分化的SCCHN,发现新的、有效的分子靶向治疗方法及其分子作用机制是很重要的治疗途径。
IGF-IR在癌症治疗中是一个新的潜在的靶点。以前也有研究证明在SCCHN中有IGF-IR过表达,而且IGF-IR信号的活化增强了头颈癌细胞的增殖、迁移。但到目前为止,通过IGF-IR的反义寡核苷酸单独或与化疗药对SCCHN进行联合治疗的效果未曾有报道,本研究试图通过下调IGF-IR的表达来观察对IGF-IR通路的抑制能否增强化疗药对SCCHN的敏感性。IGF-IR的硫代磷酸反义寡核苷酸(phosphorothioate antisense oligonucleotides, AS[S]ODN)下调了IGF-IR的表达,抑制TU159和183A细胞增殖,减弱了IGF-IR的磷酸化及其下游信号通路的活化。AS[S]ODN提高了化疗药物对TU159和183A细胞的抑制作用,增强了化疗药阿霉素诱导的细胞凋亡。体内实验发现,AS[S]ODN增强了阿霉素对TU159肿瘤的抑制作用。
IGF-IR is a membrane-bound tyrosine kinase receptor that plays a critical role in tumor cell proliferation, differentiation and apoptosis. The IGF-IR expression was constitutively low in normal hepatocytes and overexpressed in HCC. And what's more, the level of ligand IGF-Ⅱis highly expressed in many human malignancies, including breast cancer, pediatric tumors, colon cancer and HCC. Therefore, IGF-IR is an attractive anti-tumor target for HCC.Because of high homology to insulin receptor, the development of specific small molecule inhibitors of IGF-IR tyrosine kinase activity was challengeable. Recently, many specific neutralizing antibodies for IGF-IR have been researched. Although the effects of anti-tumor about theses antibodies were tested for several cell types, no comprehensive research on the anti-tumorignic impact on HCC cells have been reported to date.
Here, we generated a murine anti-IGF-IR antibody and tested our hypothesis both in vitro and in vivo by treating HCC tumor cells with the 4F2 antibody alone and in combination with the cytotoxic chemotherapeutic drugs. The anti-IGF-IR therapeutic antibody 4F2 blocks IGF-induced IGF-IR signaling and downregulates the expression of IGF-IR in HCC cells. The antitumor effect of treatment with doxorubicin could be enhanced by combining it with the 4F2.
Squamous cell carcinoma of head and neck (HNSCC) is the tenth most common cancer in worldwide. In spite of advances in recent therapies, the 5-year mortality rate of SCCHN patients has not improved in the past few decades. It is important to discover novel and effective molecular-targeted approaches. Previous studies have indicated that IGF-IR is highly expressed in human head and neck cancer and that IGF-IR signaling significantly improves the proliferation, motility, and tumorigenicity of human head and neck cancer cell lines. However, the function of IGF-IR overexpression regarding therapy in human head and neck cancer is still unclear.
In this study, we attempt to investigate whether IGF-IR downregulation results in an enhanced chemosensitive phenotype of head and neck cancer cells. Compared to phosphorothioate sense oligonucleotides (SS[S]ODN), IGF-IR phosphorothioate antisense oligonucleotides (AS[S]ODN) treatment inhibited cancer cell proliferation and attenuated activation of IGF-IR, IRS-1, Erk and Akt. IGF-IR antisense treatment was shown to enhance the sensitivity of SCCHN cell lines to doxorubicin in vitro and in vivo.
引文
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