Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells.

Fei Zhao,Jun Yan,Ming Lei,Zhe Zhang,Yangyang Han,Weiwei Huang,Lin Mao

doi:10.18632/oncotarget.6783

Abstract

Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent anti-tumor activity. Recently, triptolide was found to induce autophagy in cancer cells. However, the effects of triptolide on autophagy in human prostate cancer (PCa) cells have not yet been clearly elucidated. In this study, we demonstrated that triptolide induces autophagy in three PCa cell lines, PC-3, LNCaP and C4–2. Furthermore, we found that triptolide mediates intracellular accumulation of free calcium by stimulating the endoplasmic reticulum (ER) stress response. This activates the CaMKKβ-AMPK signaling pathway, which in turn inhibits mTOR and activates both ULK1 and Beclin 1, finally resulting in autophagy. Moreover, we found that treatment with autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) enhances triptolide-induced PCa cell death and growth inhibition. Using a PC-3-xenografted mouse model, we showed that blocking autophagy with CQ significantly promoted triptolide-induced tumor growth inhibition in vivo. Overall, our results show that triptolide induces protective autophagy through the CaMKKβ-AMPK pathway in PCa cells, implying that a combination of triptolide with autophagy inhibitors may potentially be an effective therapeutic strategy for PCa.

Highlights

Triptolide, a diterpene triepoxide, is the major active compound extracted from a traditional Chinese medicinal herb named thunder god vine (Tripterygium wilfordii Hook F.), which is mainly used to treat autoimmune diseases including rheumatoid arthritis, psoriasis and lupus
These results indicate that triptolide may induce autophagy in prostate cancer (PCa) cells
These results prove that triptolide induces autophagy in PCa cells

Summary

Introduction

Triptolide, a diterpene triepoxide, is the major active compound extracted from a traditional Chinese medicinal herb named thunder god vine (Tripterygium wilfordii Hook F.), which is mainly used to treat autoimmune diseases including rheumatoid arthritis, psoriasis and lupus. Triptolide shows potent antitumor effects, which has attracted much attention and has been studied intensively. Many studies have demonstrated that triptolide has broad-spectrum anti-tumor efficacy. Triptolide shows anti-tumor effects on almost all kinds of cancer cell in vitro and in vivo, including breast cancer, lung cancer, pancreatic cancer, colon cancer, thyroid cancer, leukemia, and so on [1,2,3,4]. Our previous studies demonstrated that triptolide has effective anti-PCa and antilaryngocarcinoma activity [5, 6]. Titov et al reported that triptolide inhibits the proliferation of all 60 cancer cell lines from the US National Cancer Institute with an average IC50 of just 12 nM [7]

Methods

Results

Conclusion