Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells

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作者：

RE Bakin，D Gioeli，RA Sikes，EA Bissonette，MJ Weber

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摘要：

Progression of ultimately results in a disease that is refractory to hormone ablation therapy but nevertheless continues to require the . 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 /-activated protein (MAP) kinase pathway as part of their signaling activities. This raises the possibility that chronic activation of /MAP kinase signaling could cause or contribute to the progression of . 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 effector-loop mutants that activate the /MAP kinase pathway is sufficient to reduce the requirement of LNCaP cells for growth, prostate-specific antigen expression, and tumorigenicity. We propose that chronic activation of endogenous c-by autocrine and paracrine growth factor stimulation sensitizes the transcriptional complex to subphysiological levels of . This provides a common mechanism for progression driven by diverse .

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关键词：

Humans Prostatic Neoplasms Anilides Nitriles ras Proteins Prostate-Specific Antigen Androgen Antagonists Mitogen-Activated Protein Kinases Androgens Mutation