Insights of RKIP-Derived Suppression of Prostate Cancer

SIMPLE SUMMARY: Despite an intensive research effort in the past few decades, prostate cancer (PC) remains a top cause of cancer death in men, particularly in the developed world. The major cause of fatality is the progression of local prostate cancer to metastasis disease. Treatment of patients with metastatic prostate cancer (mPC) is generally ineffective. Based on the discovery of mPC relying on androgen for growth, many patients with mPC show an initial response to the standard of care: androgen deprivation therapy (ADT). However, lethal castration resistant prostate cancers (CRPCs) commonly develop. It is widely accepted that intervention of metastatic progression of PC is a critical point of intervention to reduce PC death. Accumulative evidence reveals a role of RKIP in suppression of PC progression towards mPC. We will review current evidence and discuss the potential utilization of RKIP in preventing mPC progression. ABSTRACT: Prostate cancer (PC) is a major cause of cancer death in men. The disease has a great disparity in prognosis. Although low grade PCs with Gleason scores ≤ 6 are indolent, high-risk PCs are likely to relapse and metastasize. The standard of care for metastatic PC (mPC) remains androgen deprivation therapy (ADT). Resistance commonly occurs in the form of castration resistant PC (CRPC). Despite decades of research efforts, CRPC remains lethal. Understanding of mechanisms underpinning metastatic progression represents the overarching challenge in PC research. This progression is regulated by complex mechanisms, including those regulating PC cell proliferation, epithelial–mesenchymal transition (EMT), and androgen receptor (AR) signaling. Among this PC metastatic network lies an intriguing suppressor of PC metastasis: the Raf kinase inhibitory protein (RKIP). Clinically, the RKIP protein is downregulated in PC, and showed further reduction in mPC. In xenograft mouse models for PC, RKIP inhibits metastasis. In vitro, RKIP reduces PC cell invasion and sensitizes PC cells to therapeutic treatments. Mechanistically, RKIP suppresses Raf-MEK-ERK activation and EMT, and modulates extracellular matrix. In return, Snail, NFκB, and the polycomb protein EZH2 contribute to inhibition of RKIP expression. In this review, we will thoroughly analyze RKIP’s tumor suppression actions in PC.