title: Activation of the MAPK11/12/13/14 (p38 MAPK) pathway regulates the transcription of autophagy genes in response to oxidative stress induced by a novel copper complex in HeLa cells.
abstract: Transition metal copper (Cu) can exist in oxidized or reduced states in cells, leading to cytotoxicity in cancer cells through oxidative stress. Recently, copper complexes are emerging as a new class of anticancer compounds. Here, we report that a novel anticancer copper complex (HYF127c/Cu) induces oxidative stress-dependent cell death in cancer cells. Further, transcriptional analysis revealed that oxidative stress elicits broad transcriptional changes of genes, in which autophagy-related genes are significantly changed in HYF127c/Cu-treated cells. Consistently, autophagy was induced in HYF127c/Cu-treated cells and inhibitors of autophagy promoted cell death induced by HYF127c/Cu. Further analysis identified that the MAPK11/12/13/14 (formerly known as p38 MAPK) pathway was also activated in HYF127c/Cu-treated cells. Meanwhile, the MAPK11/12/13/14 inhibitor SB203580 downregulated autophagy by inhibiting the transcription of the autophagy genes MAP1LC3B, BAG3, and HSPA1A, and promoted HYF127c/Cu-induced cell death. These data suggest that copper-induced oxidative stress will induce protective autophagy through transcriptional regulation of autophagy genes by activation of the MAPK11/12/13/14 pathway in HeLa cells.
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery; Beijing Institute of Pharmacology and Toxicology; Beijing, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery; Beijing Institute of Pharmacology and Toxicology; Beijing, China; Synthetic and Functional Biomolecules Center; College of Chemistry and Molecular Engineering; Peking University; Beijing, China.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Radiology; Affiliated Hospital of the Academy of Military Medical Science; Beijing, China.
authors.forename: Fugeng
authors.initials: F
authors.lastname: Sheng
authors.affiliation: Laboratory Animal Centre; Peking University; Beijing, China.
authors.forename: Yonglu
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery; Beijing Institute of Pharmacology and Toxicology; Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Centre for Human Disease Genomics; Peking University; Beijing, China.
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery; Beijing Institute of Pharmacology and Toxicology; Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Synthetic and Functional Biomolecules Center; College of Chemistry and Molecular Engineering; Peking University; Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D013312:Stress, Physiological / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007093:Imidazoles; D009363:Neoplasm Proteins; D011725:Pyridines; D003300:Copper; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: HYF127c/Cu; MAPK11; MAPK12; MAPK13; MAPK14; autophagy; copper; oxidative stress; p38 mitogen-activated protein kinase; transcription