title: Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution.
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.
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, China.|School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xu
authors.affiliation: TCM Integrated Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Jing
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Quanshi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Chih
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Zhujiang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Diao
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Yuanliang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, China.|School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002018:Bufanolides / Q000008:administration & dosage / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002018:Bufanolides; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D051028:bcl-2-Associated X Protein; C055393:arenobufagin; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D019311:Staurosporine; D002945:Cisplatin
keywords: Bax; DRP1; PGAM5L; cancer; intrinsic apoptosis