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RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival.
Mol Cancer Res. 2015 Feb; 13(2):348-57.MC

Abstract

Prostate cancer has a proclivity to metastasize to bone. The mechanism by which prostate cancer cells are able to survive and progress in the bone microenvironment is not clear. Identification of molecules that play critical roles in the progression of prostate cancer in bone will provide essential targets for therapy. Ribosomal S6 protein kinases (RSK) have been shown to mediate many cellular functions critical for cancer progression. Whether RSK plays a role in the progression of prostate cancer in bone is unknown. IHC analysis of human prostate cancer specimens showed increased phosphorylation of RSK in the nucleus of prostate cancer cells in a significant fraction of human prostate cancer bone metastasis specimens, compared with the primary site or lymph node metastasis. Expression of constitutively active myristylated RSK in C4-2B4 cells (C4-2B4/RSK) increased their survival and anchorage-independent growth compared with C4-2B4/vector cells. Using an orthotopic bone injection model, it was determined that injecting C4-2B4/RSK cells into mouse femurs enhanced their progression in bone compared with control cells. In PC3-mm2 cells, knockdown of RSK1 (RPS6KA1), the predominant RSK isoform, but not RSK2 (RPS6KA2) alone, decreased anchorage-independent growth in vitro and reduced tumor progression in bone and tumor-induced bone remodeling in vivo. Mechanistic studies showed that RSK regulates anchorage-independent growth through transcriptional regulation of factors that modulate cell survival, including ING3, CKAP2, and PTK6. Together, these data provide strong evidence that RSK is an important driver in prostate cancer progression in bone.

IMPLICATIONS

RSK, an important driver in prostate cancer progression in bone, has promising potential as a therapeutic target for prostate cancer bone metastasis.

Authors+Show Affiliations

Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Medicine, Baylor College of Medicine, Houston, Texas.Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. slin@mdanderson.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25189355

Citation

Yu, Guoyu, et al. "RSK Promotes Prostate Cancer Progression in Bone Through ING3, CKAP2, and PTK6-mediated Cell Survival." Molecular Cancer Research : MCR, vol. 13, no. 2, 2015, pp. 348-57.
Yu G, Lee YC, Cheng CJ, et al. RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival. Mol Cancer Res. 2015;13(2):348-57.
Yu, G., Lee, Y. C., Cheng, C. J., Wu, C. F., Song, J. H., Gallick, G. E., Yu-Lee, L. Y., Kuang, J., & Lin, S. H. (2015). RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival. Molecular Cancer Research : MCR, 13(2), 348-57. https://doi.org/10.1158/1541-7786.MCR-14-0384-T
Yu G, et al. RSK Promotes Prostate Cancer Progression in Bone Through ING3, CKAP2, and PTK6-mediated Cell Survival. Mol Cancer Res. 2015;13(2):348-57. PubMed PMID: 25189355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival. AU - Yu,Guoyu, AU - Lee,Yu-Chen, AU - Cheng,Chien-Jui, AU - Wu,Chuan-Fen, AU - Song,Jian H, AU - Gallick,Gary E, AU - Yu-Lee,Li-Yuan, AU - Kuang,Jian, AU - Lin,Sue-Hwa, Y1 - 2014/09/04/ PY - 2014/9/6/entrez PY - 2014/9/6/pubmed PY - 2016/3/30/medline SP - 348 EP - 57 JF - Molecular cancer research : MCR JO - Mol. Cancer Res. VL - 13 IS - 2 N2 - UNLABELLED: Prostate cancer has a proclivity to metastasize to bone. The mechanism by which prostate cancer cells are able to survive and progress in the bone microenvironment is not clear. Identification of molecules that play critical roles in the progression of prostate cancer in bone will provide essential targets for therapy. Ribosomal S6 protein kinases (RSK) have been shown to mediate many cellular functions critical for cancer progression. Whether RSK plays a role in the progression of prostate cancer in bone is unknown. IHC analysis of human prostate cancer specimens showed increased phosphorylation of RSK in the nucleus of prostate cancer cells in a significant fraction of human prostate cancer bone metastasis specimens, compared with the primary site or lymph node metastasis. Expression of constitutively active myristylated RSK in C4-2B4 cells (C4-2B4/RSK) increased their survival and anchorage-independent growth compared with C4-2B4/vector cells. Using an orthotopic bone injection model, it was determined that injecting C4-2B4/RSK cells into mouse femurs enhanced their progression in bone compared with control cells. In PC3-mm2 cells, knockdown of RSK1 (RPS6KA1), the predominant RSK isoform, but not RSK2 (RPS6KA2) alone, decreased anchorage-independent growth in vitro and reduced tumor progression in bone and tumor-induced bone remodeling in vivo. Mechanistic studies showed that RSK regulates anchorage-independent growth through transcriptional regulation of factors that modulate cell survival, including ING3, CKAP2, and PTK6. Together, these data provide strong evidence that RSK is an important driver in prostate cancer progression in bone. IMPLICATIONS: RSK, an important driver in prostate cancer progression in bone, has promising potential as a therapeutic target for prostate cancer bone metastasis. SN - 1557-3125 UR - https://www.unboundmedicine.com/medline/citation/25189355/RSK_promotes_prostate_cancer_progression_in_bone_through_ING3_CKAP2_and_PTK6_mediated_cell_survival_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=25189355 DB - PRIME DP - Unbound Medicine ER -