Androgen receptor survival signaling is blocked by anti-beta2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells.
A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5'-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-beta2-microglobulin monoclonal antibody (beta2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. beta2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, beta2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, beta2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the beta2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing beta2M by beta2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression.
Huang
Wen-Chin
WC
Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. wen-chin.huang@cshs.org
Zhau
Haiyen E
HE
Chung
Leland W K
LW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D005227:Fatty Acids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D001613:beta 2-Microglobulin; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D017430:Prostate-Specific Antigen