The cross-talk between GSK-3β, RKIP, and PTEN as potential targets for therapeutic implications in cancer: a...

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. The Raf kinase inhibitor protein (RKIP) has been reported to be under expressed in many cancers and plays a role in the regulation of tumor cells' survival, proliferation, invasion, and metastasis, hence, a tumor suppressor. RKIP also regulates tumor cell resistance to cytotoxic drugs/cells. Likewise, the tumor suppressor, phosphatase and tensin homolog (PTEN), which inhibits the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway, is either mutated, under expressed, or deleted in many cancers and shares with RKIP its anti-tumor properties and its regulation in resistance. Several pathways are regulated by RKIP, GSK-3, PTEN, and the transcriptional and post-transcriptional regulations of RKIP, GSK-3, and PTEN are significantly altered in cancers. In addition, RKIP, GSK-3 and PTEN play a key role in the regulation of tumor cells response to chemotherapy and immunotherapy. In this review, we will focus on the roles that GSK-3, PTEN, and RKIP play in various human cancers. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mechanistic target of rapamycin complex 1 (mTORC1), nuclear Factor kappa-B (NF-κB)/Snail family transcriptional repressor 1 (Snail)/Yin Yang 1 (YY1) loop, and rat sarcoma virus oncogene (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK).