Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells.
Progression of prostate cancer ultimately results in a disease that is refractory to hormone ablation therapy but nevertheless continues to require the androgen receptor. Progression to hormone refractory disease is often correlated with overexpression of growth factors and receptors capable of establishing autocrine and/or paracrine growth-stimulatory loops. Many of these growth factor receptors engage the Ras/mitogen-activated protein (MAP) kinase pathway as part of their signaling activities. This raises the possibility that chronic activation of Ras/MAP kinase signaling could cause or contribute to the progression of prostate cancer. We have demonstrated previously that MAP kinase activation correlates with the progression to advanced hormone refractory disease in patient samples. Here we demonstrate that stable expression of Ras effector-loop mutants that activate the Ras/MAP kinase pathway is sufficient to reduce the androgen requirement of LNCaP prostate cancer cells for growth, prostate-specific antigen expression, and tumorigenicity. We propose that chronic activation of endogenous c-Ras by autocrine and paracrine growth factor stimulation sensitizes the androgen receptor transcriptional complex to subphysiological levels of androgen. This provides a common mechanism for prostate cancer progression driven by diverse agonists.
Bakin
Robert E
RE
Department of Microbiology and Cancer Center and Paul Mellon Prostate Cancer Research Institute, University of Virginia, Charlottesville, Virginia 22908, USA.
Gioeli
Daniel
D
Sikes
Robert A
RA
Bissonette
Eric A
EA
Weber
Michael J
MJ
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D000813:Anilides / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009570:Nitriles; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D014105:Tosyl Compounds; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; D020928:Mitogen-Activated Protein Kinases; D017430:Prostate-Specific Antigen; D018631:ras Proteins