title: RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival.
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.
  
  
  CONCLUSIONS
  RSK, an important driver in prostate cancer progression in bone, has promising potential as a therapeutic target for prostate cancer bone metastasis.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chien-Jui
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Chuan-Fen
authors.initials: CF
authors.lastname: Wu
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jian H
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Yu-Lee
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jian
authors.initials: J
authors.lastname: Kuang
authors.affiliation: 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.
authors.forename: Sue-Hwa
authors.initials: SH
authors.lastname: Lin
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C114988:CKAP2 protein, human; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C459806:ING3 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D019893:Ribosomal Protein S6 Kinases