Two Diseases with One Hit: Inhibiting a Potential Diabetes Target to Reduce Cancer Risk and to Improve Anti-Cancer Therapy

Abstract

Obesity is a well-recognized cancer risk factor. The increase in risk for colorectal, endometrial, breast and eso- phageal cancers associated with obesity ranges from 1.5- to as much as 3-fold. Obese patients develop more aggressive cancers that are less responsive to treatment. Here, we review the available data on an obesity-linked gene, SH2-domain- containing inositol 5-phosphatase-2 (SHIP2), in light of new experimental and clinical evidence of its pro-oncogenic role. A putative diabetes drug target, SHIP2 is an important negative regulator of insulin signaling that acts downstream of phosphoinositide 3-kinase (PI3-kinase). In mice, SHIP2 levels are increased by a high-fat diet, and its knockout prevents diet-induced obesity. Taking together these findings, we propose that SHIP2 is a potential anti-cancer target with a high therapeutic index owing to its cancer-specific overexpression and/or differential function combined with the absence of major untoward effects upon its loss of function in normal cells. We compare and contrast the pro-oncogenic function of SHIP2 with the current understanding of cancer-relevant functions of PTEN and PTP-1B, two negative regulators of insu- lin function. The provocative idea that a negative regulator of insulin function will positively influence oncogenesis pre- sents the intriguing possibility that its inhibition will be a beneficial strategy for two major therapeutic areas: metabolic diseases (such as obesity and diabetes) and cancer.