Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, PR China.
Cancer Lett. 2012 Jul 28;320(2):171-9. doi: 10.1016/j.canlet.2012.03.002. Epub 2012 Mar 8.
Induction of cell death and inhibition of cell growth are the main targets of cancer therapy. Here we evaluated the role of autophagy on chemoresistance of human hepatocarcinoma (HCC) cell lines, focusing on its crosstalk with cell apoptosis and proliferation. In this study, a chemotherapeutic agent (cisplatin or 5FU) induced the formation of autophagosomes in three human HCC cell lines and upregulated the expression of autophagy protein LC3-II. Inhibition of autophagy by 3-methyladenine or si-beclin 1 increased chemotherapy-induced apoptosis in HCC cells. Meanwhile, increased damage of the mitochondrial membrane potential was also observed in HCC cells when autophagy was inhibited. Furthermore, inhibition of autophagy reduced clone formation and impaired cell growth of HCC cells when treated with chemotherapy. Co-administration of an autophagy inhibitor (chloroquine) and chemotherapy significantly inhibited tumor growth in a mouse xenograft tumor model, with greater extent of apoptosis and impaired proliferation of tumor cells. This study suggests that autophagy is a potential novel target to improve therapy efficiency of conventional chemotherapeutics towards HCC.
诱导细胞死亡和抑制细胞生长是癌症治疗的主要目标。在这里，我们评估了自噬在人肝癌（HCC）细胞系化疗耐药中的作用，重点研究了自噬与细胞凋亡和增殖的相互作用。在这项研究中，一种化疗药物（顺铂或 5FU）在三种人肝癌细胞系中诱导自噬体的形成，并上调自噬蛋白 LC3-II 的表达。自噬的抑制作用通过 3-甲基腺嘌呤或 si-beclin 1 增加 HCC 细胞中化疗诱导的细胞凋亡。同时，当自噬被抑制时，也观察到 HCC 细胞中线粒体膜电位的损伤增加。此外，当用化疗处理时，抑制自噬会减少 HCC 细胞的克隆形成并损害细胞生长。自噬抑制剂（氯喹）与化疗药物联合应用可显著抑制小鼠异种移植肿瘤模型中的肿瘤生长，凋亡程度更大，肿瘤细胞增殖受损。这项研究表明，自噬可能是提高常规化疗药物治疗 HCC 疗效的一个新靶点。
