Article Publish Status: FREE
Abstract Title:

Withaferin A triggers G2/M arrest and intrinsic apoptosis in glioblastoma cells via ATF4-ATF3-CHOP axis.

Abstract Source:

Cell Prolif. 2020 Jan ;53(1):e12706. Epub 2019 Oct 23. PMID: 31642559

Abstract Author(s):

Qin Tang, Liwen Ren, Jinyi Liu, Wan Li, Xiangjin Zheng, Jinhua Wang, Guanhua Du

Article Affiliation:

Qin Tang


OBJECTIVE: Withaferin A (WA) is a bioactive compound with a remarkable anti-cancer effect derived from Withania somnifera, commonly known as ashwagandha. However, the anti-cancer mechanisms of WA in glioblastoma multiforme (GBM) are still unclear.

MATERIALS AND METHODS: Cell viability assays and xenografted nude mice were used to evaluate the effects of WA, along with flow cytometry to detect apoptosis and cell cycle of GBM. RNA-seq analysis, Western blotting, immunofluorescence staining, qRT-PCR and siRNA gene silencing were carried out to determine the signalling pathways affected by WA.

RESULTS: Withaferin A significantly inhibited the growth of GBM in vitro and in vivo and triggered the intrinsic apoptosis of GBM cells by up-regulating expression of Bim and Bad. WA arrested GBM cells at the G2/M phase of the cell cycle through dephosphorylating Throf CDK1 by activating p53-independent p21 up-regulation. Knockdown of p21 restored cell cycle progression and cell viability by down-regulating the expression of Bad rather than Bim. We demonstrated that endoplasmic reticulum (ER) stress induced by WA through the ATF4-ATF3-CHOP axis, initiated apoptosis and G2/M arrest in GBM cells.

CONCLUSION: We revealed a novel pathway that elucidated WA activation of apoptosis and G2/M arrest in GBM cells through the ATF4-ATF3-CHOP axis. This discovery is important for optimization of WA-based regimens for prevention and/or treatment of GBM.

Study Type : Animal Study, In Vitro Study

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