title: Chidamide Inhibits Aerobic Metabolism to Induce Pancreatic Cancer Cell Growth Arrest by Promoting Mcl-1 Degradation.
abstract: Pancreatic cancer is a fatal malignancy worldwide and urgently requires valid therapies. Previous research showed that the HDAC inhibitor chidamide is a promising anti-cancer agent in pancreatic cancer cell lines. In this study, we elucidate a probable underlying anti-cancer mechanism of chidamide involving the degradation of Mcl-1. Mcl-1 is frequently upregulated in human cancers, which has been demonstrated to participate in oxidative phosphorylation, in addition to its anti-apoptotic actions as a Bcl-2 family member. The pancreatic cancer cell lines BxPC-3 and PANC-1 were treated with chidamide, resulting in Mcl-1 degradation accompanied by induction of Mcl-1 ubiquitination. Treatment with MG132, a proteasome inhibitor reduced Mcl-1 degradation stimulated by chidamide. Chidamide decreased O2 consumption and ATP production to inhibit aerobic metabolism in both pancreatic cancer cell lines and primary cells, similar to knockdown of Mcl-1, while overexpression of Mcl-1 in pancreatic cancer cells could restore the aerobic metabolism inhibited by chidamide. Furthermore, chidamide treatment or Mcl-1 knockdown significantly induced cell growth arrest in pancreatic cancer cell lines and primary cells, and Mcl-1 overexpression could reduce this cell growth inhibition. In conclusion, our results suggest that chidamide promotes Mcl-1 degradation through the ubiquitin-proteasome pathway, suppressing the maintenance of mitochondrial aerobic respiration by Mcl-1, and resulting in inhibition of pancreatic cancer cell proliferation. Our work supports the claim that chidamide has therapeutic potential for pancreatic cancer treatment.
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.|Microbiology Laboratory, Shunyi District Center for Disease Control and Prevention, Beijing, China.
authors.forename: Mu
authors.initials: M
authors.lastname: He
authors.affiliation: Medical Research Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Kuai
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Changlan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Xingwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Xuanlin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Weijing
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Suping
authors.initials: S
authors.lastname: Ren
authors.affiliation: Department of Blood Products and Substitutes, Beijing Institute of Transfusion Medicine, Beijing, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D007976:Leupeptins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D025801:Ubiquitin; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde