Roles of androgen-dependent and -independent activation of signal transduction pathways for cell proliferation of prostate cancer cells

Abstract

Prostate cancer is one of the most frequently diagnosed cancers in the western world and this malignant neoplasm is the second-leading cause of cancer death among men in the USA. In the early 1940s, Huggins and Hodges demonstrated that growth and survival of prostate cancer depends on androgens. The mainstay of treatment for advanced prostate cancer is currently androgen ablation. Over the past few decades, several compounds, such as luteinizing hormone-releasing hormone analogues and anti-androgens, were developed and widely used in clinics. Then, the new treatment strategy, maximum androgen blockade (MAB) was introduced. In fact, MAB improved the prognosis of patients with advanced prostate cancer to some extent; however, most of those patients finally relapse after a period of initial response to this therapy, developing androgen-independent prostate cancer (AIPC). Once patients develop AIPC, effective therapeutic modalities are extremely limited and, therefore, the prognosis of this disease is very poor. It is strongly desirable to explore novel therapeutic concepts for AIPC, based on detailed molecular mechanisms for progression to androgen independency. As for the molecular mechanisms involved in the emergence of AIPC, mutations in the androgen receptor have been examined most extensively. These days, evidence is accumulating that demonstrates activation of signal transduction pathways, such as Src, PI3K and mTOR/S6K, are involved in the acquisition of the androgen-independent cell proliferation of prostate cancer cells. In addition, animal models using transgenic and gene-knockout techniques have confirmed these results. The development of therapies targeting against the signal transduction pathways is critical for the improvement of the prognosis of patients with AIPC. In this article, we review recent understandings on molecular mechanisms of androgen-dependent proliferation of prostate cancer cells, whose aberrant activation is proposed as a critical event for progression to AIPC.

Keywords: PKCζ; S6 kinase; androgen receptor; androgen-independent prostate cancer; c-Src; genotropic pathways; nongenotropic pathways; prostate cancer; signal transduction pathway.