Role of PTP1b in the Regulation of Free Fatty acids Flux that Promotes Cancer Pathogenesis: Lipolysis and Lipogenesis

Recent studies support the concept that obesity is associated with different forms of cancers. PTP1B is a major negative regulator of the Insulin receptor and JAK2 kinase acting downstream of leptin and growth hormone signaling, and thus an important mediator towards the pathogenesis of diabetes and obesity. More recently, it was also found to act as an oncogene in breast cancer. Human studies have also reported that PTP1B levels are increased with diabetes, obesity and cancer making this enzyme an exceptional drug target. Obesity is characterized by excessive fat deposition and increased free fatty acids (FFA) into the circulation. FFA may also contribute to the development of some cancers, on the basis that FFA concentrations are elevated in several cancer patients. Despite a growing interest in the oncogenic contribution of FFA, the metabolic basis for this correlation remains unclear. In this context dysregulated de novo FFA biosynthesis pathway is due in large part, to increased expression and activity of fatty acid synthase (FAS), a key lipogenic enzyme. Increased expression of hormone sensitive lipase (HSL) has been also shown to be a major cause in enhanced lipolysis in cancer cachexia. We present data suggesting that PTP1B may play a crucial role in developing obesity and insulin resistance through the control of expression and activity of specific lipases involved in the pathway hydrolyzing triacylglycerols into FFA and glycerol. We believe that PTP1B act in the control of FFA levels in cancer cells, through the regulation of lipases and in promoting the production of FFA‐derived signaling molecules that contribute to tumor growth.