Targeting SHIP1 and SHIP2 in Cancer

Abstract

Membrane-anchored and soluble inositol phospholipid species are critical mediators of intracellular cell signaling cascades. Alterations in their normal production or degradation are implicated in the pathology of a number of disorders including cancer and pro-inflammatory conditions. The SH2-containing 5’ inositol phosphatases, SHIP1 and SHIP2, play a fundamental role in these processes by depleting PI(3,4,5)P3, but also by producing PI(3,4)P2 at the inner leaflet of the plasma membrane. With the intent of targeting SHIP1 or SHIP2 selectively, or both paralogs simultaneously, small molecule inhibitors and agonists have been developed and tested in vitro and in vivo over the last decade in various disease models. These studies have shown promising results in various pre-clinical models of disease including cancer and tumor immunotherapy. In this review the potential use of SHIP inhibitors in cancer is discussed with particular attention to the molecular structure, binding site and efficacy of these SHIP inhibitors.

Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions

“…Ship2 is a Phosphatidylinositol (PtdIn) 5-phosphatase which converts PI(3,4,5)P 3 (i.e., PhosphatidylInositol(3,4,5)trisPhosphate) into PI(3,4)P 2 (i.e., PhosphatidylInositol(3,4)bisPhosphate) by removing the phosphate group at the 5 position of the inositol unit [ 168 , 169 ]. PtdIns possess acyl chains through which they are engaged to the inner side of the plasma membrane [ 170 ]. A few PtdIns, like PI(4,5)P2, PI(3,4,5)P3 and PI(3,4)P2, play a pivotal role for triggering signaling cascades, as a variety of enzymes, including intracellular kinases and scaffolding proteins, can be selectively engaged by them for example through pleckstrin homology (PH) domains [ 170 ].…”

“…PtdIns possess acyl chains through which they are engaged to the inner side of the plasma membrane [ 170 ]. A few PtdIns, like PI(4,5)P2, PI(3,4,5)P3 and PI(3,4)P2, play a pivotal role for triggering signaling cascades, as a variety of enzymes, including intracellular kinases and scaffolding proteins, can be selectively engaged by them for example through pleckstrin homology (PH) domains [ 170 ]. Ship2 plays first of all a well-known role in glucose metabolism [ 171 ], and it is considered a target for the treatment of type 2 diabetes, as, by downregulating PI(3,4,5)P3 levels, it suppresses PI3K-mediated insulin signaling pathway [ 172 ].…”

“…Nevertheless, Ship2 acts as modulator of the PI3K(PhosphoInositide 3-Kinase)/AKT signaling pathway whose relationship to cell survival, proliferation, effector function and vesicle trafficking is well established [ 170 ]. The proto-oncogene serine-threonine kinase AKT (also known as PKB) contains a PH domain able to interact with both PI(3,4,5)P3 and PI(3,4)P2 with different affinity: these two PtIns are necessary for full AKT activation [ 170 ]. The presence of both PI(3,4,5)P3 and PI(3,4)P2, through the enhanced AKT activation, supports cancer cells to escape inherent cell death machinery [ 170 ].…”

“…The proto-oncogene serine-threonine kinase AKT (also known as PKB) contains a PH domain able to interact with both PI(3,4,5)P3 and PI(3,4)P2 with different affinity: these two PtIns are necessary for full AKT activation [ 170 ]. The presence of both PI(3,4,5)P3 and PI(3,4)P2, through the enhanced AKT activation, supports cancer cells to escape inherent cell death machinery [ 170 ]. However, as concerning the correlation between Ship2 and cancer, it is controversial and dependent on the cancer cell type [ 168 ].…”

“…Ship2 levels are high in several breast cancer cell lines like MDA-231, where Ship2 over-expression favors cell survival, proliferation and tumor growth [ 171 ] while, Ship2 silencing causes anti-proliferative effects [ 168 ]. Generally, increased levels of Ship2 characterize glioma, breast and colon cancers and have been related to a poor prognosis due to improved cell migration and invadopodia maturation leading to enhanced metastatic capacity [ 170 , 171 ]. In contrast to these pro-cancer functions, Ship2 negatively regulates cancer cell progression in gastric cancer cell lines [ 171 ].…”