Parathyroid hormone related-protein promotes epithelial-to-mesenchymal transition in prostate cancer.
Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer.
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, California, United States of America.
Weg M
WM
Ongkeko
Department of Medicine, Veterans Administration San Diego Healthcare System, University of California San Diego, La Jolla, California, United States of America.
Doug
D
Burton
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, California, United States of America.
Alan
A
Kiang
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, California, United States of America.
Eric
E
Abhold
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, California, United States of America.
Selena Z
SZ
Kuo
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, California, United States of America.
Elham
E
Rahimy
AntiCancer, Inc., San Diego, California, United States of America.
Meng
M
Yang
AntiCancer, Inc., San Diego, California, United States of America.
Robert M
RM
Hoffman
Department of Pathology, University of California San Diego and the Veterans Administration San Diego Healthcare System, San Diego, California, United States of America.
Jessica
J
Wang-Rodriguez
Department of Medicine, Veterans Administration San Diego Healthcare System, University of California San Diego, La Jolla, California, United States of America.
Leonard J
LJ
Deftos
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014183:Transplantation, Heterologous; D014746:Vimentin / Q000235:genetics
D015820:Cadherins; D044162:Parathyroid Hormone-Related Protein; D020033:Protein Isoforms; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D020780:Matrix Metalloproteinase 9