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

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

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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 (mitogenactivated 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.

Original languageEnglish (US)
Pages (from-to)296-310
Number of pages15
JournalAutophagy
Volume10
Issue number2
DOIs
StatePublished - Feb 2014

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Dong, Y., Yin, S., Jiang, C., Luo, X., Guo, X., Zhao, C., Fan, L., Meng, Y., Lu, J., Song, X., Zhang, X., Chen, N., & Hu, H. (2014). 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. Autophagy, 10(2), 296-310. https://doi.org/10.4161/auto.27210