title: TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival by regulation of endoplasmic reticulum chaperone expression.
abstract: Endocrine therapy is the standard treatment for advanced prostate cancer; however, relapse occurs in most patients with few treatment options available after recurrence. To overcome this therapeutic hurdle, the identification of new molecular targets is a critical issue. The capability to proliferate in three-dimensional (3D) conditions is a characteristic property of cancer cells. Therefore, factors that regulate 3D growth are considered rational targets for cancer therapy. Here, we applied a functional genomic approach to the 3D spheroid cell culture model and identified TRIB1, a member of the Trib family of serine/threonine kinase-like proteins, as an essential factor for prostate cancer cell growth and survival. RNAi-mediated silencing of TRIB1 suppressed prostate cancer cell growth selectively under the 3D conditions. This effect was rescued by ectopic expression of an RNAi-resistant TRIB1 exogene. Gene signature-based analysis revealed that TRIB1 was related to endoplasmic reticulum (ER) pathways in prostate cancer and was required for expression of the ER chaperone GRP78, which is critical for prostate tumorigenesis. Of note, GRP78 was expressed preferentially in a subpopulation of prostate cancer cells that possess tumor-propagating potential, and these tumor-propagating cells were highly sensitive to TRIB1 and GRP78 depletion. In a xenograft model of human prostate cancer, TRIB1 depletion strongly inhibited tumor formation. Supporting these observations, we documented frequent overexpression of TRIB1 in clinical specimens of prostate cancer. Overall, our results indicated that the TRIB1-ER chaperone axis drives prostate tumorigenesis and the survival of the tumor-propagating cells.
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Tetsuo
authors: T
authors: Mashima
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Taeko
authors: T
authors: Soma-Nagae
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Molecular Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Toshiro
authors: T
authors: Migita
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
authors: Ryoko
authors: R
authors: Kinoshita
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Iwamoto
authors: Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Takeshi
authors: T
authors: Yuasa
authors: Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Junji
authors: J
authors: Yonese
authors: Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Yuichi
authors: Y
authors: Ishikawa
authors: Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Tokyo, Japan. hseimiya@jfcr.or.jp.
authors: Hiroyuki
authors: H
authors: Seimiya
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000235:genetics* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C493170:TRIB1 protein, human; D017346:Protein Serine-Threonine Kinases