Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
Autophagy. 2010 Oct;6(7):997-8. doi: 10.4161/auto.6.7.13334. Epub 2010 Oct 16.
Pancreatic cancer, the fourth leading cause of cancer-related death in the United States, is resistant to current chemotherapies. Therefore, identification of different pathways of cell death is important to develop novel therapeutics. Our previous study has shown that triptolide, a diterpene triepoxide, inhibits the growth of pancreatic cancer cells in vitro and prevents tumor growth in vivo. However, the mechanism by which triptolide kills pancreatic cancer cells was not known, hence, this study aimed at elucidating it. Our study reveals that triptolide kills diverse types of pancreatic cancer cells by two different pathways; it induces caspase-dependent apoptotic death in some cell lines and death via a caspase-independent autophagic pathway in the other cell lines tested. Triptolide-induced autophagy requires autophagy-specific genes, atg5 or beclin 1 and its inhibition results in cell death via the apoptotic pathway, whereas inhibition of both autophagy and apoptosis rescues triptolide-mediated cell death. Our study shows for the first time that induction of autophagy by triptolide has a pro-death role in pancreatic cancer cells. Since triptolide kills diverse pancreatic cancer cells by different mechanisms, it makes an attractive chemotherapeutic agent for future use against a broad spectrum of pancreatic cancers.
胰腺癌是美国癌症相关死亡的第四大主要原因，对当前的化疗具有耐药性。因此，确定细胞死亡的不同途径对于开发新的治疗方法很重要。我们之前的研究表明，雷公藤红素是一种二萜三环氧，可抑制体外胰腺癌细胞的生长并防止体内肿瘤生长。然而，雷公藤红素杀死胰腺癌细胞的机制尚不清楚，因此，本研究旨在阐明这一点。我们的研究表明，雷公藤红素通过两种不同的途径杀死不同类型的胰腺癌细胞；它在一些细胞系中诱导依赖半胱天冬酶的凋亡性死亡，而在其他测试的细胞系中则通过非依赖半胱天冬酶的自噬途径死亡。雷公藤红素诱导的自噬需要自噬特异性基因，atg5 或 beclin 1，其抑制导致通过凋亡途径的细胞死亡，而同时抑制自噬和凋亡可挽救雷公藤红素介导的细胞死亡。我们的研究首次表明，雷公藤红素诱导的自噬在胰腺癌细胞中具有促进死亡的作用。由于雷公藤红素通过不同的机制杀死不同的胰腺癌细胞，因此它成为未来针对广泛胰腺癌症的有吸引力的化疗药物。
