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SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors.

ABSTRACT: SHIP2 (Src homology 2 domain-containing inositol 5'-phosphatase 2) belongs to the family of 5'-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5'-position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first-line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

SUBMITTER: Lehtonen S

PROVIDER: S-EPMC6916339 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors.

Lehtonen Sanna S

Acta physiologica (Oxford, England) 20190812 1

SHIP2 (Src homology 2 domain-containing inositol 5'-phosphatase 2) belongs to the family of 5'-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5'-position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and ty ...[more]

PMID: 31342643

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Project description:ObjectiveThere is increasing pre-clinical and clinical evidence that metformin, a commonly used diabetes medication, has a protective effect in cancer. The aim of this review is to discuss metformin's anti-cancer molecular mechanisms of action and to summarize the current literature demonstrating metformin's potential in gynecologic cancer prevention and treatment.MethodsA PubMed search was conducted combining the keywords "metformin" with "neoplasm", "uterine neoplasms", "ovarian neoplasms", and "uterine cervical neoplasms". Studies published in English between 1994 and 2014 were included.ResultsPre-clinical studies in endometrial, ovarian, and cervical cancer suggest that metformin inhibits the growth of cancer cells. The primary molecular mechanism mediating this effect appears to be the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of mammalian targets of rapamycin (mTOR). The pre-clinical findings are augmented by clinical studies indicating that metformin use is associated with a reduced risk of cancer and improved survival in diabetic women with ovarian and endometrial cancers. No clinical analyses have evaluated metformin use and cervical cancer. Overall, the data showing a favorable effect of metformin is strongest for endometrial and ovarian cancer and prospective clinical testing is ongoing in these two malignancies.ConclusionsNumerous clinical studies have reported an association between metformin use by diabetic patients and improved outcomes in gynecologic cancers. In addition, pre-clinical reports have identified plausible biological mechanisms to explain the molecular mechanism of action of metformin in cancer. However, the most important question remains unanswered: Will metformin be effective against cancer in patients without diabetes? Until this question is answered with prospective clinical testing, the role of metformin in the treatment or prevention of gynecologic malignancies remains theoretical and the clinical use of metformin as a cancer therapeutic is experimental.

Dataset Information

SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors.

Publications

SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors.

Similar Datasets

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