The biological complexity of RKIP signaling in human cancers

Abstract

The Raf kinase inhibitory protein (RKIP) has been demonstrated to modulate different intracellular signaling pathways in cancers. Studies have shown that RKIP is frequently downregulated in cancers; therefore, attempts have been made to upregulate the expression of RKIP using natural and synthetic agents for the treatment of human malignancies. Moreover, various regulators such as specific proteins and microRNAs (miRNAs) that are involved in the regulation of RKIP expression have also been identified. RKIP mechanistically modulates the apoptotic regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. Because of its critical role in human cancers, RKIP has drawn much research attention, and our understanding is expanding rapidly. Here, we summarize some of the biological complexities of RKIP regulation. However, we restrict our discussion to selected tumors by focusing on TRAIL, miRNAs and natural agents. Emerging evidence suggests a role for natural agents in RKIP regulation in cancer cells; therefore, naturally occurring agents may serve as cancer-targeting agents for cancer treatment. Although the literature suggests some advancement in our knowledge of RKIP biology, it is incomplete with regard to its preclinical and clinical efficacy; thus, further research is warranted. Furthermore, the mechanism by which chemotherapeutic drugs and novel compounds modulate RKIP and how nanotechnologically delivered RKIP can be therapeutically exploited remain to be determined.

RKIP Regulates Differentiation-Related Features in Melanocytic Cells

“…Among others, this signature included altered expression pattern of the oncogenes KIT, BCL3, MAF, MYC, MYCL, HOXA9, CDC25B, and PIM1. In our data, all of them showed a two to five-fold increase, supporting the role for RKIP like a tumor suppressor gene [54]. Interestingly enough, downregulation of RKIP expression on melanocytes resulted in the alteration of cellular processes intimately linked to malignant transformation of cells, such as development and differentiation.…”

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

“…These can be either synthetic drugs or natural agents, but treatment options also include specific proteins and microRNAs, as mentioned above [11]. …”

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

“…This multifunctional capacity of RKIP is associated with its involvement in the modulation of several signalling pathways (Reviewed at [4][5][6][7][8]). This protein was first described as a regulator of the Raf-MEK-ERK pathway, acting as its endogenous inhibitor.…”

“…Due to its important role as a modulator of intracellular signalling pathways that control several cellular processes, the deregulated expression of RKIP is implicated in several pathologies, including cancer [4,6]. The first association between RKIP and cancer was established in prostate metastatic cell lines, in which cellular RKIP expression levels were lower when compared to primary tumour cell lines [15].…”