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

// Wenjuan Xu 1, 2, * , Linlin Jing 3, * , Quanshi Wang 1, * , Chung-Chih Lin 4 , Xiaoting Chen 5 , Jianxin Diao 2 , Yuanliang Liu 2 , Xuegang Sun 1, 2 1 Nanfang Hospital, Southern Medical University, Guangzhou, China 2 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China 3 TCM Integrated Hospital of Southern Medical University, Guangzhou, China 4 Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan 5 Zhujiang 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.