title: Autophagy-mediated HMGB1 release antagonizes apoptosis of gastric cancer cells induced by vincristine via transcriptional regulation of Mcl-1.
abstract: Autophagy-associated release of HMGB1 is known to protect cancer cells from many chemotherapeutics. However, the detailed molecular mechanism(s) responsible remains largely undefined. We show in this study that HMGB1 released into the extracellular space protects gastric cancer cells from apoptosis induced by the microtubule-targeting drug vincristine through transcriptional upregulation of Mcl-1. Extracellular HMGB1 appeared essential for autophagy-mediated inhibition of apoptosis, in that siRNA knockdown of HMGB1 or inhibition of its release abolished the protective effect of autophagy. Strikingly, vincristine upregulated the Mcl-1 mRNA expression through a transcriptional increase, but did not alter the expression levels of the Mcl-1 protein. Inhibition of HMGB1 release blocked the increase in the Mcl-1 transcript and caused reduction in Mcl-1 at the protein level, indicating that HMGB1-mediated signaling was necessary for transcriptional upregulation of Mcl-1. This seemed critical for maintaining sufficient Mcl-1 protein expression required for survival of gastric cancer cells exposed to vincristine. The effect of extracellular HMGB1 on transcriptional regulation of Mcl-1 was confirmed in gastric cancer cells treated with recombinant HMGB1. Taken together, these results identify HMGB1-mediated upregulation of Mcl-1 transcription as an important mechanism by which autophagy protects gastric cancer cells from apoptosis induced by vincristine.
authors: Department of Immunology; Anhui Medical University; Hefei, Anhui China.
authors: ZhenZhen
authors: Z
authors: Zhan
authors: Qun
authors: Q
authors: Li
authors: Ping
authors: P
authors: Wu
authors: Yan
authors: Y
authors: Ye
authors: Hsin-Yi
authors: HY
authors: Tseng
authors: Linjie
authors: L
authors: Zhang
authors: Xu Dong
authors: XD
authors: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D024243:HMGB1 Protein; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014750:Vincristine