Abstract LB-51: TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival via the regulation of endoplasmic reticulum chaperone expression

Abstract

Abstract Androgen deprivation therapy is the standard treatment for advanced prostate cancer. However, relapse occurs in most patients, and there are few treatment options available after recurrence. While the androgen receptor (AR) signaling is still often active in the castration-resistant prostate cancer, minor subsets of the AR-negative, prostate tumor-propagating/cancer stem-like cells have also been reported. Therefore, to eradicate advanced prostate cancer, which presumably contains the AR-negative tumor-propagating cells, identification of new molecular targets is a critical issue. In this study, we aimed to identify factors that support the tumor-propagating potential of prostate cancer cells. The capability to proliferate in three-dimensional (3D) conditions is a characteristic property of cancer cells. Especially, tumor-propagating cells have a higher capability to proliferate under 3D spheroid culture conditions. Therefore, factors that regulate the 3D growth are considered rational targets for cancer therapy. Here, we employed a functional genomic approach to the 3D spheroid cell culture model and identified TRIB1, a member of the Trib family serine/threonine kinase-like proteins, as an essential factor for the tumor-propagating potential of human prostate cancer cells. We found that short hairpin RNA (shRNA)-mediated knockdown of TRIB1 suppressed the AR-positive and negative prostate cancer cell growth under 3D but not conventional adherent culture conditions. This effect was rescued by ectopic expression of the shRNA-resistant TRIB1 exogene. Transcriptome and gene signature-based analyses revealed that TRIB1 was closely related to the endoplasmic reticulum (ER) pathways in prostate cancer and was required for the expression of the ER chaperone GRP78, which is critical for prostate tumorigenesis. Of note, GRP78 was preferentially expressed in a CD166/CD151/TRA-1-60 triple positive subpopulation, which possessed tumor-propagating potential, and these tumor-propagating cells were highly sensitive to TRIB1 and GRP78 depletion. TRIB1 depletion severely inhibited tumor formation in a prostate tumor xenograft model. Consistent with these observations, quantitative PCR and immunohistochemical analyses revealed that TRIB1 was frequently overexpressed in clinical prostate cancer specimens. These results indicate that the TRIB1-ER chaperone axis supports prostate tumorigenesis and the survival of the tumor-propagating cells. Strategies that target this axis may be utilized as a novel therapeutics for eradication of advanced prostate cancer. Citation Format: Tetsuo Mashima, Taeko Soma-Nagae, Toshiro Migita, Ryoko Kinoshita, Atsushi Iwamoto, Takeshi Yuasa, Junji Yonese, Yuichi Ishikawa, Hiroyuki Seimiya. TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival via the regulation of endoplasmic reticulum chaperone expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-51. doi:10.1158/1538-7445.AM2014-LB-51