Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

• Published in: Journal of cellular biochemistry Vol. 118; no. 4; pp. 891 - 902
• Main Authors: Cackowski, Frank C., Eber, Matthew R., Rhee, James, Decker, Ann M., Yumoto, Kenji, Berry, Janice E., Lee, Eunsohl, Shiozawa, Yusuke, Jung, Younghun, Aguirre‐Ghiso, Julio A., Taichman, Russell S.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2017
• Subjects: Animals; AXL; c-Mer Tyrosine Kinase; Cell Cycle; Cell Line, Tumor; Cell Survival; DISSEMINATED TUMOR CELL; DORMANCY; Gene Knockdown Techniques; Heterografts; Histones - metabolism; Humans; Male; MAP Kinase Signaling System; MERTK; Methylation; Mice; Mice, SCID; Neoplasm Recurrence, Local - enzymology; Neoplasm Recurrence, Local - pathology; PROSTATE CANCER; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - secondary; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Escape; Tumor Microenvironment; TYRO3; TYRO3; PROSTATE CANCER; DORMANCY; MERTK; AXL; DISSEMINATED TUMOR CELL
• ISSN: 0730-2312; 1097-4644; 1097-4644
• DOI: 10.1002/jcb.25768

ABSTRACT Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL, and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P‐Erk1/2 to P‐p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knockdown of MERTK in PCa cells increased metastasis free survival in an intra‐cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates PCa dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation. J. Cell. Biochem. 118: 891–902, 2017. © 2016 Wiley Periodicals, Inc. Escape from cellular dormancy is the process where previously dormant single disseminated tumor cells reactivate to form cancer micro‐metastases, which continue to grow and ultimately make the disease incurable. Here, were show that Mer tyrosine kinase is important for prostate cancer dormancy escape through a mechanism involving MAP kinases, cell cycle inhibitors, epigenetics, and transcription factors associated with pluripotent cells.