摘要
非小细胞肺癌是一种非常恶性的癌症,五年存活率只有15%。治疗方式现在主要包括手术治疗,放射治疗,化学治疗等,其中,化学治疗是一种主要的治疗方式。我们利用非小细胞肺癌细胞为模型,研究小分子药物pemetrexed(培美曲塞)和salermide诱导细胞凋亡的分子机制。
细胞凋亡信号通路主要包括线粒体介导的内源性凋亡通路以及死亡受体介导的外源性凋亡通路。促凋亡蛋白Bid可以介导外源性和内源性凋亡信号通路之间的联系。DR5(Death Receptor5,死亡受体5)是一个非常重要的TRAIL受体蛋白,可以激活外源性凋亡信号介导的凋亡通路。DR5通过与衔接蛋白FADD结合,招募下游蛋白pro-caspase-8,形成凋亡诱导信号复合体(Death-inducing signaling complex)并导致caspase-8的活化。一方面caspase-8可以激活下游效应蛋白caspase-3,-6,-7,诱导细胞凋亡。另一方面,在某些细胞中,caspase-8可以剪切活化Bid(形成tBid),活化的Bid从细胞质转移到线粒体并且活化线粒体介导的细胞凋亡信号转导途径。
一些肿瘤治疗的药物可以特异性诱导肿瘤细胞中DR5的表达。异常表达的DR5在肿瘤凋亡方面起着重要的作用。细胞受到外界胁迫时,DR5可以在没有配体存在的条件下活化,激活细胞凋亡信号通路,导致细胞凋亡。此外,一些转录因子可以调控DR5表达,比如Spl, AP1, p53, NFkB, YYl以及CHOP。其中,CHOP可以结合到DR5启动子区域,诱导DR5表达。此外,CHOP在内质网应激(Endoplasmic Reticulum (ER) stress)信号转导通路中发挥了重要作用,CHOP在内质网应激信号通路中持续异常表达可以导致细胞周期阻滞和细胞凋亡。
内质网应激是细胞对外界刺激作出的一种反应。静息状态下,内质网内的分子伴侣蛋白(Bip)与内质网膜上的感受器蛋白(IRE1α,PERK, ATF6)结合,保持内质网的稳态。当细胞持续受到外界胁迫时,大量的错误折叠蛋白产生并且会在内质网中累积,Bip与这些错误折叠蛋白结合并且释放内质网膜上的感受器蛋白,解离后的IRE1α,PERK以及ATF6活化以后可以介导内质网应激下游信号通路。
首先,PERK与Bip解离以后可以通过二聚化以及磷酸化修饰激活,进而通过eIF2α (translation-initiation factor eIF2a)特异性增加ATF4的转录,ATF4可以调控下游基因的表达,比如ATF3, CHOP。ATF3(活化转录因子3)和ATF4(活化转录因子4)属于ATF/CREB家族成员(activating transcription factor/cyclic AMP response element binding protein (ATF/CREB) family),具有亮氨酸拉链结构域,可以调控内质网应激信号通路介导的细胞凋亡。
除了PERK, IREl α和ATF6也是重要的存在于内质网膜上的内质网应激感受器蛋白。IREl α与Bip解离后二聚化并具有内切核糖核酸酶的活性。它可以移除XBP1mRNA中26个碱基内含子,活化的XBP1转移至细胞核并诱导下游基因的表达。另外,ATF6与Bip解离后从内质网上释放以后,通过高尔基体以及蛋白酶体SIP和S2P的修饰,变成具有活性形式的ATF6并移至细胞核,诱导下游靶向基因的表达。
持续内质网信号通路的激活可以导致细胞凋亡。caspases的激活是细胞凋亡过程中的一个重要过程。正常状态下,caspases一般处于非活化状态。c-FLIP (cellular FLICE-inhibitory protein)是一个非常重要的凋亡抑制蛋白。死亡受体可以通过FADD(Fas associated death domain)招募caspase-8形成DISC(Death inducing signaling complex凋亡诱导信号复合体)。c-FLIP可以竞争性与FADD结合抑制caspase-8的活性。与此一致,下调c-FLIP表达可以增加死亡受体诱导细胞凋亡的概率。
培美曲塞(pemetrexed)是一种抗叶酸代谢的化合物,临床上常与顺铂(cisplatin)联合作用治疗恶性间皮细胞瘤和晚期非小细胞肺癌。培美曲塞抑制嘌呤嘧啶代谢中所需要三种酶的活力,分别是胸苷酸合酶、二氢叶酸还原酶以及甘氨酰胺核苷酸甲酰转移酶。抑制DNA的合成,破坏细胞的生长。但是培美曲塞抑制细胞生长,促进细胞凋亡的具体分子机制还没有被明确阐述。本文的目标之一是阐述培美曲塞诱导非小细胞肺癌细胞凋亡的分子机制。
我们研究发现培美曲塞可以上调死亡受体5(DR5)的表达,重组肿瘤坏子因子相关凋亡诱导配体(TRAIL)蛋白与培美曲塞具有协同作用,使用两种药物同时处理非小细胞肺癌细胞可以明显增加细胞凋亡的百分率。使用siRNA抑制DR5表达可以减弱培美曲塞诱导的细胞凋亡。这也进一步验证了DR5在其中的作用。此外,我们发现抑制C/EBP同源蛋白(CHOP)可以减少DR5表达。FLICE抑制蛋白(c-FLIP)是凋亡相关蛋白caspase-8的抑制剂,过表达c-FLIP降低培美曲塞诱导的细胞凋亡百分率。通过以上实验结果我们认为DR5和C-FLIP蛋白在培美曲塞诱导非小细胞肺癌细胞凋亡的过程中发挥了重要作用。
利用非小细胞肺癌细胞作为模型,我们研究了另外一种小分子化合物对细胞凋亡的影响。Salermide是一种新合成的特异性抑制sirtuinl (sirtl)和sirtuin2(sirt2)的小分子化合物,虽然研究表明salermide可以诱导细胞凋亡,但是具体的分子机制仍然并不清楚。我们以中国高发的非小细胞肺癌(NSCLC)作为研究模型,发现salermide可以诱导死亡受体5(Death Receptor5)的表达上调,进而激活凋亡前体蛋白pro-caspase-8, pro-caspase-9以及凋亡效应蛋白caspase-3,导致多聚ADP核糖多聚糖(PARP)活性降低。进一步研究发现,内质网应激信号通路的激活在salermide诱导的NSCLC细胞凋亡中起到了重要作用。内质网应激蛋白IRE1-α, Bip, ATF3(活化转录因子3),ATF4(活化转录因子4),CHOP受salermide刺激表达上调,抑制Sirtl1和sirt2的表达也可以得到相同的结果。并且使用基因沉默方法分别抑制ATF3,ATF4和CHOP的表达后,salermide诱导非小细胞肺癌细胞的凋亡减弱。通过以上实验,我们认为salermide激活内质网应激信号通路,诱导ATF4, ATF3以及CHOP的表达,导致DR5水平上调,最终导致非小细胞肺癌细胞的凋亡。这项研究不但进一步验证了内质网应激信号通路以及DR5活性对于非小细胞肺癌细胞的凋亡起着重要的调控作用,为以DR5以及内质网应激信号通路蛋白作为分子靶标治疗非小细胞肺癌提供理论上的依据,并且发现同时抑制sirtuinl和sirtuin2可以诱导非小细胞肺癌细胞的凋亡。
除了非小细胞肺癌,我们对卡波西肉瘤的发生机制进行了研究。卡波西肉瘤(Kaposi sarcoma)是一种恶性肿瘤,在非洲的一些国家,艾滋病患者以及免疫系统较弱的人群中发病率较高,并且有很高的致死率。卡波西肉瘤常发病于皮肤,粘膜以及淋巴结等部位。卡波西肉瘤疱疹病毒(Kaposi sarcoma-associated herpesvirus, KSHV, HHV-8)是引发卡波西肉瘤原因,卡波西肉瘤一般起源于内皮淋巴细胞。在免疫系统正常的人群中,卡波西肉瘤疱疹病毒感染不会引发疾病。在美国和欧洲的一些发达国家,高效抗逆转录病毒疗法(Highly active antiretroviral therapy (HAART))(?)能够有效治疗艾滋病人群中卡波西肉瘤患者,但是在非洲一些不发达的国家依旧有非常高的发病率和致死率。
截止到目前,KSHV的致癌机制并不是非常清楚。KSHV编码的基因中,病毒G蛋白偶联受体(viral G-protein-coupled receptor (vGPCR))具有强烈的致癌性。它可以诱导内皮细胞的恶性转化。一些转基因老鼠模型,比如TIE2-tva内皮特异性vGPCR转基因老鼠,表明过表达vGPCR可以诱发KS样肿瘤。vGPCR是一种可以持续活化的非配体依赖性的七次跨膜蛋白。但是一些配体,比如CXCL1(chemokine (C-X-C motif) ligand1)以及CXCL3(chemokine (C-X-C motif) ligand3)可以增强vGPCR活性。
vGPCR可以诱导内皮细胞的恶性转化。很多信号通路可以被vGPCR激活。比如vGPCR可以激活PI3K γ的活性并诱导肿瘤生成,NFkB在vGPCR诱导的肿瘤生成过程中也发挥了重要作用。此外,vGPCR可以诱导VEGF(vascular endothelial growth factor)的表达和分泌,促进血管生成。AKT, ERK, p38以及IKK β可以导致TSC/mTOR的活化以及HIF表达上调,激活VEGF。此外，小G蛋白在vGPCR信号转导过程中发挥了重要作用,比如Racl,抑制Racl活性可以阻止vGPCR诱导的NFkB, AP-1以及NFAT的活化,抑制肿瘤生成。异常表达Racl可以诱导KS样肿瘤生成。此外,在动物模型中,内皮特异性敲除Racl影响内皮细胞的功能和血管的发育。
Hippo肿瘤抑制信号通路是一条重要的控制器官大小的信号通路。Hippo信号通路的失调会导致细胞增殖,肿瘤发生。Hippo信号通路的主要蛋白包括MST1/2, Latsl/2,以及YAP/TAZ. MST1/2活化Latsl/2后,磷酸化的Latsl/2可以抑制YAP/TAZ的活性,促进蛋白酶体依赖性的蛋白降解。相反,去磷酸化的YAP/TAZ定位在细胞核并且与TEAD家族转录因子结合,控制下游基因的表达,促进细胞存活和增殖。许多研究表明YAP/TAZ在癌症发生发展过程中起着非常重要的作用。稳定转基因过表达YAP的老鼠可以导致组织增生以及肿瘤发生。
在很多种恶性肿瘤中发现YAP/TAZ异常表达并且定位于细胞核。因此,YAP/TAZ在肿瘤发生发展中发挥了重要作用。但是,调控YAP/TAZ的上游信号转导机制尚不清楚。我们研究发现在卡波西肉瘤中YAP/TAZ高度异常表达活化。KSHV编码的vGPCR通过调控Hippo信号通路导致肿瘤发生。抑制YAP/TAZ表达可以明显抑制vGPCR诱导的肿瘤形成。
总之,我们的研究一方面阐述了小分子化合物诱导肿瘤细胞凋亡的分子机制,激活内质网应激信号通路在小分子诱导NSCLC细胞凋亡过程中起到重要作用,具体的分子机制需要进一步研究。另一方面通过对卡波西肉瘤研究,我们发现YAP/TAZ被卡波西肉瘤疱疹病毒激活并且在卡波西肉瘤的发生发展过程中起到重要作用。
Non-small cell lung carcinoma (NSCLC) is the most common cancer in the United States (>200,000cases/year), and carries a dismal5years15%survival. Surgery is available for a limited number of patients, and chemotherapy remains the mainstay of therapy for this disease. One part of this thesis is tried to figure out the mechanism of apoptosis in NSCLC cells induced by small molecular drugs, such as pemetrexed and salermide.
There are two major apoptosis signalling pathways:the intrinsic mitochondria-mediated pathway and the extrinsic death receptor-induced pathway. The truncated form of the pro-apoptotic protein Bid serves as the cross-talk between these two pathways. Death Receptor5(DR5) is an important mediator of the extrinsic apoptotic signalling pathway. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) binds DR5and preferentially induces apoptosis in transformed cells while sparing normal cells, in contradistinction to other mediators of programmed cell death such as TNF and FasL. DR5expression is inducible by cancer therapeutic and preventive agents, and up-regulation of DR5often explains induction of programmed cell death or augmentation of TRAIL-induced apoptosis. The trimeric activated DR5will recruit the adaptor molecule (FADD) and Pro-caspase-8to form death-inducing signaling complex (DISC). Caspase-8will be activated and lead to the activation of executioner caspases (caspase-3,-6, and-7) in type I cells. In type II cells, Bid was cleaved by the activated caspase-8and translocated from the cytoplasm to the mitochondria, leading to the apoptosis induced by mitochondria.
In times of cellular stress, DR5expression can be induced without ligand-receptor interactions, resulting in a ligand-independent activation of the death receptor-mediated apoptotic signalling pathway. Some of the most powerful inducers of DR5transcription that circumvent TRAIL-DR5 interactions include high local concentrations of Sp1, AP1, p53, NFkB, YY1and C/EBP homologous protein (CHOP, also known as growth arrest and DNA damage gene153(GADD153)). CHOP is one of the most potent inducer of DR5and downstream apoptosis, and CHOP is frequently released during the endoplasmic reticulum (ER) stress response. CHOP is typically undetectable in physiological conditions; however, it is dramatically increased during periods of ER stress, resulting in cell cycle arrest and ultimately apoptosis.
ER stress is one kind of signaling pathway in response to the stress. In non-stressed cells, Bip (the ER chaperone) binds to the luminal domains of the IRE1a, PERK and ATF6, which are the ER-stress sensors, remaining these proteins in an inactive state. When ER stress is induced by the accumulation of unfolded or misfolded proteins, Bip will combine with the proteins instead of binding with IRE1a, PERK and ATF6, which are major proteins of ER stress. The release of Bip leads to the activation of PERK by homodimerization and trans-autophosphorylation, which phosphorylates the translation-initiation factor elF2α and enhances the transcription of the ATF4mRNA. Some target genes, such as ATF3and CHOP, were induced by the activated ATF4.
Both activating transcription factor3(ATF3) and activating transcription factor4(ATF4) belong to the activating transcription factor/cyclic AMP response element binding protein (ATF/CREB) family of basic region-leucine zipper (bZip) transcription factors. ATF3is an adaptive-response gene that participates in cellular processes by activating or repressing specific gene expression. Whereas previous studies have revealed that ATF4plays an important role in regulating CHOP, it is still unclear weather ATF3also plays an important role in CHOP, thereafter DR5regulation.
Besides PERK, IRE1α and ATF6are also major effector proteins involved in ER stress. IRE1α dissociates with Bip and dimerization to induce the activity.26-base intron of XBP1mRNA will be removed by IRE1α and the active XBP1encodes the expression of ER stress target genes. In addition, the release of Bip allows ATF6to translocate to the Golgi apparatus and cleaved by the proteases S1P and S2P, resulting in the active ATF6fragment (ATF6p50), which will translocate to the nucleus and activate the transcription of ER stress target genes.
A central step in the execution of apoptosis is the activation of caspases, which are widely present as inactive forms. Cellular FLICE-inhibitory protein (c-FLIP) is the pivotal protein that negatively modulates the caspase cascade. Specifically, caspase-8is activated by death receptors through Fas associated death domain (FADD) binding of the death inducing signalling complex (DISC). Thus, the primary role of c-FLIP is a specific inhibitor of death receptor-mediated apoptosis. Accordingly, down-regulation of c-FLIP confers sensitivity to death receptor-induced apoptosis. Although multiple splicing isoforms of c-FLIP mRNA have been reported, c-FLIPL and c-FLIPs, are major splicing variants detectable at the protein level and have been extensively characterised.
Pemetrexed is a clinically available anti-folate therapeutic agent used in combination with cisplatin for the management of patients with malignant pleural mesothelioma and advanced non-small cell lung cancer. Pemetrexed inhibits three enzymes in purine and pyrimidine synthesis necessary for precursor DNA nucleotides which in turn disrupts growth and survival of normal and cancer cells. The mechanism by which pemetrexed induces apoptosis remains largely uncharacterised. In the current study, we examined the downstream effect of pemetrexed in inducing apoptosis in lung cancer cells. We showed that pemetrexed induced apoptosis via up-regulation of Death Receptor5(DR5), an important death receptor for tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). In addition, we discovered a synergistic effect of combination pemetrexed and recombinant TRAIL in inducing apoptosis. Modulating DR5induction by small interfering RNA abrogated the ability of pemetrexed to induce apoptosis. In addition, silencing of C/EBP homologous protein (CHOP) expression reduced DR5expression, demonstrating that the transcriptional factor CHOP has a pivotal role on DR5 up-regulation following pemetrexed treatment. In addition, enforced expression of cellular FLICE-inhibitory protein (c-FLIP), a known inhibitor of caspase8, protected neoplastic cells from apoptosis despite pemetrexed and/or TRAIL therapy. This work demonstrates the efficacy and mechanistic underpinnings of pemetrexed-induced apoptosis, and they suggest pemetrexed may have clinical utility when used in combination with TRAIL for the management of patients with lung cancer.
Another chemical we use is salermide, a reverse amide compound, which inhibits Sirtuin1(Sirt1) and Sirtuin2(Sirt2), has been shown to induce apoptosis in human cancer cells. The mechanism underlying cellular apoptotic signalling by salermide remains unclear. In this study, we show that salermide up-regulates the expression of death receptor5(DR5) in human non-small cell lung cancer (NSCLC) cells. Blocking DR5expression by gene silencing technology results in a decrease in activated forms of several pro-apoptotic proteins (caspase-8, caspase-9, caspase-3, PARP). Increasing DR5protein expression correlates with salermide-induced apoptosis in human NSCLC cells. We discovered that IRE-1a, Bip, activating transcription factor3(ATF3), activating transcription factor4(ATF4) and C/EBP homologous protein (CHOP) are induced by salermide, which suggests that DR5-dependent apoptosis is induced by endoplasmic reticulum stress. Moreover, knockdown of Sirt1and Sirt2expression resulted in up-regulation of ATF4, CHOP and DR5. Transfected NSCLC cells with ATF4, ATF3or CHOP siRNA results in a decline in proapoptotic proteins (such as caspase-8, caspase-9, caspase-3and PARP) despite salermide treatment. We demonstrate that salermide induces expression of ATF4, and ATF4up-regulates ATF3and subsequently modulates CHOP. This suggests that DR5is modulated by the ATF4-ATF3-CHOP axis in NSCLC after Sirt112inhibition or salermide treatment, indicating the importance of DR5up-regulation in apoptosis induced by Sirt1/2inhibition and elucidates the underlying mechanism in human NSCLC cells.
Another research focus in my thesis is about the development of Kaposi sarcoma (KS), which occurs frequently in people living in Equatorial Africa. It is also a common cancer diagnosed in human immunodeficiency virus (HIV) carriers or patients under immunosuppression. KS is typically found on the skin, mouth, gastrointestinal tract, and lymph node. Growth rates and size of the tumor vary among patients, and can be life-threatening. Kaposi sarcoma-associated herpesvirus (KSHV, also referred to as HHV-8) has been identified as the infectious agent responsible for KS. The incidence of KS in HIV-infected individuals in the United States has been decreasing due to effective highly active antiretroviral therapy (HAART). However, it remains high morbidity and mortality in AIDS patients and some sub-Saharan African countries.
KSHV encodes a viral G-protein-coupled receptor (vGPCR) that has been shown to be sufficient to induce neoplastic transformation of endothelial cells. vGPCR has high basal signaling activity, which can be further enhanced via ligands like CXCL1(chemokine (C-X-C motif) ligand1) and CXCL3(chemokine (C-X-C motif) ligand3). Mouse models, such as transgenic mice expressing vGPCR and endothelial-specific vGPCR gene transduction (TIE2-tva transgenic mice), have revealed that the vGPCR-induced tumors are remarkably similar to KS, suggesting vGPCR initiates KS. However, the precise molecular mechanism involved in KSHV-induced Kaposi sarcoma is still unclear.
A complicated signaling network is mediated by vGPCR, which contributes to the oncogenic transform of endothelial cells. For example, Pl3Ky is activated by vGPCR and has an important role in vGPCR-induced sarcomagenesis, while NFkB plays a role in vGPCR-induced paracrine neoplasia. In addition, vGPCR dramatical amplification of VEGF secretion by avtivation of AKT, ERK, p38and IKKp, results in the TSC/mTOR activation and HIF upregulation. Furthermore, Heterotrimeric G-proteins are required to relay GPCR signals to downstream effectors. It has been reported small G protein Rac1is activated by vGPCR. Repressing Rac1expression blocks the induction of the NFκB, AP-1, and NFAT activity and inhibits vGPCR sarcomagenesis in vivo. Moreover, expression of Rac1is sufficient to generate KS-like tumors in mouse. Furthermore, the endothelial cell-specific animal model reveals that deletion of Rac1disrupts the endothelial cell function and vascular development.
The Hippo tumor-suppressor pathway is fundamental in regulating organ size, and dysregulation promotes cell proliferation and tumorigenesis. Within the Hippo pathway, MST1/2kinases phosphorylate and activate the Lats1/2kinases, which in turn phosphorylate and inhibit the transcription co-activators YAP/TAZ. YAP and TAZ are transcription co-activators with oncogenic potential and their inhibition represents the major functional output of the Hippo pathway. Lats dependent phosphorylation inhibits YAP/TAZ by inducing nuclear exclusion and proteasome dependent degradation. On the contrary, dephosphorylated YAP/TAZ localize to the cell nucleus associating with TEAD family transcriptional factors (TEAD1-4) to stimulate gene expression, particularly genes involved in cell survival and proliferation. Extensive studies have demonstrated that YAP/TAZ play important roles in cancer development. For example, transgenic YAP expression in mice induces tissue overgrowth and tumorigenesis.
Increased YAP/TAZ expression and/or nuclear localization are frequently observed in multiple human cancers. However, the mechanisms leading to YAP/TAZ activation in human cancers are largely unknown. In this report, we demonstrate that YAP and TAZ expression is highly elevated in Kaposi sarcoma. KSHV-encoded vGPCR signals through the Hippo pathway to induce oncogenic transformation. Also, downregulation of YAP/TAZ suppresses vGPCR-induced tumorigenesis, indicating a pivotal role of the Hippo pathway in the KS development.
In summary, the thesis clarifies the molecular mechanism of apoptosis in NSCLC cells induced by small molecular drugs. Endoplasmic reticulum stress may be critical in this process. In Kaposi sarcoma, we find YAP/TAZ are activated by KSHV and contribute to KSHV-induced tumorigenesis.
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