Oncotarget

Research Papers:

Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution

Wenjuan Xu, Linlin Jing, Quanshi Wang, Chung-Chih Lin, Xiaoting Chen, Jianxin Diao, Yuanliang Liu and Xuegang Sun _

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Oncotarget. 2015; 6:30017-30034. https://doi.org/10.18632/oncotarget.5013

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Abstract

Wenjuan Xu1,2,*, Linlin Jing3,*, Quanshi Wang1,*, Chung-Chih Lin4, Xiaoting Chen5, Jianxin Diao2, Yuanliang Liu2, Xuegang Sun1,2

1Nanfang Hospital, Southern Medical University, Guangzhou, China

2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China

3TCM Integrated Hospital of Southern Medical University, Guangzhou, China

4Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

5Zhujiang Hospital, Southern Medical University, Guangzhou, China

*These authors have contributed equally to this work

Correspondence to:

Xuegang Sun, e-mail: sxg_smu@126.com

Keywords: PGAM5L, Bax, DRP1, intrinsic apoptosis, cancer

Received: April 03, 2015     Accepted: August 20, 2015     Published: August 31, 2015

ABSTRACT

Intrinsic apoptosis eliminates cells with damaged DNA and cells with dysregulated expression of oncogene. PGAM5, a member of the phosphoglycerate mutase family, has two splicing variants: PGAM5L (the long form) and PGAM5S (the short form). It has been well established that PGAM5 is at the convergent point of multiple necrosis pathways. However, the role of PGAM5 in intrinsic apoptosis is still controversial. Here we report that the PGAM5L, but not PGAM5S is a prerequisite for the activation of Bax and dephosphorylation of Drp1 in arenobufagin and staurosporine induced intrinsic apoptosis. Knockdown of PGAM5L inhibits the translocation of Bax to the mitochondria and reduces mitochondrial fission. The interaction between PGAM5L and Drp1 was observed in both arenobufagin and staurosporine treated HCT116 cells, but not in HCT116 Bax−/− cells. Bax transfection rescues the formation of the triplex in both arenobufagin and staurosporine stimulated HCT116 Bax−/− cells. Arenobufagin shows remarkable anti-cancer effects both in orthotropic and heterotropic CRC models and demonstrates less toxic effects as compared with that of cisplatin. Bax-PGAM5L-Drp1 complex is detected in arenobufagin and staurosporine treated CRC cells in vitro and in arenobufagin and cisplatin treated tumor in vivo as well. In summary, our results demonstrate that Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution.


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