A New Linkage between the Tumor Suppressor RKIP and Autophagy: Targeted Therapeutics

The complexities of molecular signaling in cancer cells have been hypothesized to mediate cross-network alterations of oncogenic processes such as uncontrolled cell growth, proliferation, acquisition of epithelial-to-mesenchymal transition (EMT) markers, and resistance to cytotoxic therapies. The two biochemically exclusive processes/proteins examined in the present review are the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP) and the cell-intrinsic system of macroautophagy (hereafter referred to as autophagy). RKIP is poorly expressed in human cancer tissues, and low expression levels are correlated with high incidence of tumor growth, metastasis, poor treatment efficacy, and poor prognoses in cancer patients. By comparison, autophagy is a conserved cytoprotective degradation pathway that has been shown to influence the acquisition of resistance to hypoxia and nutrient depletion as well as the regulation of chemo-immuno-resistance and apoptotic evasion. Evidently, a broad library of cancer-relevant studies exists for RKIP and autophagy, although reports of the interactions between pathways involving RKIP and autophagy have been relatively sparse. To circumvent this limitation, the coordinate regulatory and effector mechanisms were examined for both RKIP and autophagy. Here, we propose three putative pathways that demonstrate the inherent pleiotropism and relevance of RKIP and the microtubule-associated protein 1 light chain 3 (MAP1LC3, LC3) on cell growth, proliferation, senescence, and EMT, among the hallmarks of cancer. Our findings suggest that signaling modules involving p53, signal transducer and activator of transcription 3 (STAT3), nuclear factor-κB (NF-κB), and Snail highlight the novel roles for RKIP in the control of autophagy and vice versa. The suggested potential crosstalk mechanisms are new areas of research in which to further study RKIP and autophagy in cancer models. These should lead to novel prognostic motifs and will provide alternative therapeutic strategies for the treatment of unresponsive aggressive cancer types.