Triptolide induces protective autophagy through activation of the CaMKKβ-AMPK signaling pathway in prostate cancer cells
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// Fei Zhao 1, * , Weiwei Huang 1, * , Zhe Zhang 1 , Lin Mao 1, 3 , Yangyang Han 1, 3 , Jun Yan 3 , Ming Lei 1, 2 1 College of Life Sciences, Northwest A & F University, Yangling, Shaanxi Province, People's Republic of China 2 Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, People's Republic of China 3 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, Jiangsu Province, People's Republic of China * These authors contributed equally to this work Correspondence to: Ming Lei, e-mail: leiming@ibp.ac.cn Keywords: triptolide, CaMKKβ, AMPK, autophagy, apoptosis Received: July 13, 2015 Accepted: December 05, 2015 Published: December 29, 2015 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.
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Triptolide induces autophagy-mediated caspase-independent cell death in tumor cells.
“Furthermore, TPL has been shown to induce autophagy-mediated caspase-independent cell death in tumor cells.”
From Drug repurposing for cancer therapy (2024) · cites this paper as [91]
The Results section (‘Triptolide induces cytoprotective autophagy in PCa cells’; page not supplied) concludes that autophagy protects prostate cancer cells from triptolide-induced death: inhibiting autophagy increased both cell death and caspase-3 cleavage. This is contrary to the attributed claim that triptolide-induced autophagy mediates caspase-independent cell death. (LLM, conf=0.90)
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- Authors
- Zhao, F., Huang, W., Zhang, Z., Mao, L., Han, Y., Yan, J., & Lei, M.
- Affiliations
- Northwest A&F University (CN)
- Model Animal Research Center (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Zhao, Fei
- Huang, Weiwei
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-12-29
- Volume
- 7
- Issue
- 5
- Pages
- 5366-5382
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4868692
- OpenAlex
- W2232593830
- Cited by
- 77
- References
- 50
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 12 · 2020: 5 · 2019: 7 · 2018: 13 · 2017: 8 · 2016: 7
- FWCI
- 18.97
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31571194)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- triptolide, prostate cancer, autophagy, CaMKKβ, AMPK signaling, endoplasmic reticulum stress, intracellular calcium accumulation, mTOR inhibition, ULK1, Beclin-1, apoptosis, chloroquine, 3-methyladenine, xenograft tumor growth, Tripterygium wilfordii, anticancer natural products
- MeSH terms
- Animals, Anti-Inflammatory Agents, Non-Steroidal, Autophagy, Diterpenes, Epoxy Compounds, Humans, Immunoenzyme Techniques, Male, Mice, Nude, Phenanthrenes, Prostatic Neoplasms, RNA, Messenger, Tumor Cells, Cultured, Blotting, Western, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases, Endoplasmic Reticulum Stress, Real-Time Polymerase Chain Reaction
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