Hyaluronan stimulates transformation of androgen-independent prostate cancer.
Interaction between extracellular matrices and cancer cell receptors frequently alters signal transduction pathways, leading to malignant transformation and metastasis. Hyaluronan (HA) is a tumor promoter and enhancer in transformation of androgen-independent (AI) prostate cancer (CaP); however, the signal transduction pathway involved in this mechanism remains unclear. We report here that HA-mediated CD168, a receptor for HA-mediated motility, and its downstream signal molecules, including ROK1, Gab-1, PI3K*p110alpha and eIF4E3, accelerate the progression of AI rather than androgen-dependent CaP and enhance AI cell invasion and metastasis in human bone marrow endothelial layers. MicroRNA-based small hairpin RNA-mediated suppression of ROK1 can reverse the malignant role of CD168 signaling in human AI CaP PC3 and DU145 cells. This differential activation of ROK-PI3K signaling in AI CaP cells may provide clues to shed light on some mechanisms of cancer relapse after androgen ablation. These findings reveal a novel signal transduction mechanism for matrix-mediated cancer transformation and metastasis in hormone-refractory CaP.
Lin
Shi-Lung
SL
Department of Cell and Neurobiology, Keck School of Medicine BMT-403, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA. lins@usc.edu
Chang
Donald
D
Ying
Shao-Yao
SY
D000728:Androgens / Q000502:physiology*; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005819:Genetic Markers; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D000728:Androgens; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid