Involvement of autophagy induction in penta-1,2,3,4,6-O-galloyl-β-D-glucose-induced senescence-like growth arrest in human cancer cells.

Abstract

Growing evidence has demonstrated that autophagy plays important and paradoxical roles in carcinogenesis, while senescence is considered to be a crucial tumor-suppressor mechanism in cancer prevention and treatment. In the present study we demonstrated that both autophagy and senescence were induced in response to penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG), a chemopreventive polyphonolic compound, in multiple types of cancer cells. Analysis of these 2 events over the experimental time course indicated that autophagy and senescence occurred in parallel early in the process and dissociated later. The long-term culture study suggested that a subpopulation of senescent cells may have the capacity to reenter the cell cycle. Inhibition of autophagy by either a chemical inhibitor or RNA interference led to a significant reduction of PGG-induced senescence, followed by induction of apoptosis. These results suggested that autophagy promoted senescence induction by PGG and that PGG might exert its anticancer activity through autophagy-mediated senescence. For the first time, these findings uncovered the relationships among autophagy, senescence, and apoptosis induced by PGG. In addition, we identified that unfolded protein response signaling played a pivotal role in the autophagy-mediated senescence phenotype. Furthermore, our data showed that activation of MAPK8/9/10 (mitogen-activated protein kinase 8/9/10/c-Jun N-terminal kinases) was an essential upstream signal for PGG-induced autophagy. Finally, the key in vitro results were validated in vivo in a xenograft mouse model of human HepG2 liver cancer. Our findings provided novel insights into understanding the mechanisms and functions of PGG-induced autophagy and senescence in human cancer cells.

• Authors: Yinhui Dong, Shutao Yin, Cheng Jiang, Xiaohe Luo, Xiao Guo, Chong Zhao, Lihong Fan, Yubing Meng, Junxuan Lu, Xinhua Song, Xudong Zhang, Ni Chen, Hongbo Hu
• Journal: Autophagy (Autophagy) Vol. 10 Issue 2 Pg. 296-310 (Feb 2014) ISSN: 1554-8635 [Electronic] United States
• PMID: 24389959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrolyzable Tannins
• pentagalloylglucose
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Humans
• Hydrolyzable Tannins (pharmacology)
• JNK Mitogen-Activated Protein Kinases (drug effects)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (pathology)