Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells

Biochemical Pharmacology
Kapil SharmaSekhar Majumdar

Abstract

Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor is known to inhibit the growth of various cancer cells including melanoma. Here in this study, we have found that PTX induces autophagy in human melanoma cell lines (A375 and MeWo). Induction of autophagy is associated with the increase in Atg5 expression as knockdown of Atg5 effectively inhibited PTX mediated autophagy. A decrease in mTOR activation was also observed after PTX treatment. We observed that autophagy was activated as a downstream effector mechanism of ER stress induced by PTX. ER stress response was confirmed by upregulation of IRE-1α, GRP78 and CHOP expression. PTX treatment also resulted in an increase in intracellular calcium (Ca(2+)) level. Ca(2+) is the central player as blocking Ca(2+) by intracellular calcium chelator (BAPTA-AM) effectively inhibited the PTX induced ER stress response as well as autophagy. Moreover, silencing of CHOP also resulted in autophagy inhibition with a decrease in Atg5 expression. Collectively, PTX triggers ER stress response followed by induction of autophagy via involvement of Ca(2+)→CHOP→Atg5 signalling cascade. Interestingly, inhibition of intracellular calcium level by BAPTA-AM significantly increased PTX mediat...Continue Reading

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Citations

Jul 5, 2016·Oncogene·N SkalkaR Rosin-Arbesfeld
Oct 30, 2016·Biochemical Pharmacology·Heather Graham Hambright, Rita Ghosh
Oct 11, 2017·Molecular Medicine Reports·Pian-Pian ChenYing-Zheng Zhao
Feb 14, 2018·International Journal of Oncology·Yessica Cristina Castellanos-EsparzaHe Lu
May 1, 2021·Frontiers in Molecular Biosciences·Shulong CaoHaiyuan Zhang
Dec 31, 2021·Journal of Medicinal Chemistry·Yan GuoXiaoyong Wang

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