SIK2: A critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer

Abstract

Aim To explore the role of salt‐inducible kinase 2 (SIK2) on glucose and lipid metabolism in ovarian cancer (OC), so as to increase the understanding of potential inhibitors targeting SIK2 and lay a foundation for future precision medicine in OC patients. Methods We reviewed and summarized the regulation effect of SIK2 on glycolysis, gluconeogenesis, lipid synthesis, and fatty acids β‐oxidation (FAO) in OC, as well as the potential molecular mechanism and the prospects of potential inhibitors targeting SIK2 in future cancer treatments. Results Many pieces of evidence show that SIK2 is closed associated with glucose and lipid metabolism of OC. On the one hand, SIK2 enhances the Warburg effect by promoting glycolysis and inhibiting oxidative phosphorylation and gluconeogenesis, on the other hand, SIK2 regulates intracellular lipid metabolism through promoting lipid synthesis and FAO, all of which ultimately induces growth, proliferation, invasion, metastasis, and therapeutic resistance of OC. On this basis, SIK2 targeting may become a new solution for the treatment of a variety of cancer types including OC. The efficacy of some small molecule kinase inhibitors has also been demonstrated in tumor clinical trials. Conclusion SIK2 displays significant effects in OC progression and treatment through regulating cellular metabolism including glucose and lipid metabolism. Therefore, future research needs to further explore the molecular mechanisms of SIK2 in other types of energy metabolism in OC, based on this to develop more unique and effective inhibitors.

Glucose metabolism reprogramming in gynecologic malignant tumors

“…Hu's study concluded that SIK2 not only enhances the Warburg effect by promoting glycolysis, inhibiting oxidative phosphorylation and gluconeogenesis, but also regulates intracellular lipid metabolism by promoting lipid synthesis and FAO. Ultimately, this leads to growth, proliferation, invasion, metastasis and therapeutic resistance in OC 122 . Additionally, molecules such as HSP70, SATB1, PSMD14, and STAT3 regulate glucose metabolism through different mechanisms or signaling cascades in OC, which promotes cancer progression and results in poor prognosis 84 , 87 , 94 , 95 .…”

The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity

“…Furthermore, several neurological functions have recently been reported to be controlled by SIK, including circadian rhythmicity. In addition, an imbalance in SIK function has been associated with several types of cancer ( 3 , 4 , 5 , 6 ). Although the three SIK isoforms share similar structures and targets, they play both distinct and redundant roles in regulating physiological processes.…”