title: TBK1 regulates prostate cancer dormancy through mTOR inhibition.
abstract: The mechanisms that regulate hematopoietic stem cell (HSC) dormancy and self-renewal are well established and are largely dependent on signals emanating from the HSC niche. Recently, we found that prostate cancer (PCa) cells target the HSC niche in mouse bone marrow (BM) during metastasis. Little is known, however, as to how the HSC niche may regulate dormancy in cancer cells. In this study, we investigated the effects of TANK binding kinase 1 (TBK1) on PCa dormancy in the BM niche. We found that binding with niche osteoblasts induces the expression of TBK1 in PCa cells PC3 and C4-2B. Interestingly, TBK1 interacts with mammalian target of rapamycin (mTOR) and inhibits its function. Rapamycin, an mTOR inhibitor, induces cell cycle arrest of PCa cells and enhances chemotherapeutic resistance of PCa cells. As a result, the knockdown of TBK1 decreases PCa stem-like cells and drug resistance in vitro and in vivo. Taken together, these results strongly indicate that TBK1 plays an important role in the dormancy and drug resistance of PCa.
authors.affiliation: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI.
authors.forename: Jin Koo
authors.initials: JK
authors.lastname: Kim
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Wang
authors.forename: Jeena
authors.initials: J
authors.lastname: Joseph
authors.forename: Anjali
authors.initials: A
authors.lastname: Mishra
authors.forename: Elliott E
authors.initials: EE
authors.lastname: Hill
authors.forename: Paul H
authors.initials: PH
authors.lastname: Krebsbach
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shiozawa
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051550:I-kappa B Kinase / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010006:Osteoblasts / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D010455:Peptides; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D020123:Sirolimus
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