Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche

Abstract

The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85α-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer.

How to make ovarian cancer cells “sick-too”

“…This identified SIK2 as an important activator of the fatty acid oxidation pathway. 6 These studies suggest that adipocyte-mediated SIK2 phosphorylation and protein stabilization are required to activate cancer cell proliferation and fatty acid oxidation at the omental metastatic niche (Fig. 1).…”

“…We showed that siRNA-mediated depletion of SIK2 or its chemical inhibition significantly reduced rapamycininduced AKT phosphorylation and sensitized ovarian cancer cells to its cytotoxic effect. 6 Importantly, calcium-dependent activation of SIK2 was independent from LKB1 indicating that LKB1 is not a unique regulator of SIK2 but that other kinases may activate it downstream of an increase in intracellular calcium depending on the cell type and context of activation. This is reminiscent of the previously reported activation of AMPK by CAMKK through direct phosphorylation of T172 at the T-loop of the AMPK kinase, a site that is also phosphorylated by LKB1.…”

“…Depletion of endogenous SIK2 in xenograft models of ovarian cancer significantly reduced ovarian cancer metastasis. 6 These findings are important because, they identify SIK2 as a plausible therapeutic target for prevention of ovarian cancer metastasis and, possibly, tumor recurrence.…”

“…5 More recently we revealed a previously unrecognized role of SIK2 for driving ovarian cancer cell metabolism and proliferation at the adipocyte-rich environment of the abdominal cavity. 6 We proposed a key role for SIK2 in establishing abdominal metastases following nutritional deprivation of free-floating cancer cells in the peritoneal cavity (Fig. 1).…”

Cancer metastasis: issues and challenges

“…In the original reports of these genes’ pro-metastatic functions, JAM2 was studied in melanoma [6], PPARGC1A [7] and TRAF6 [8] were studied in breast cancer, and SIK2 was studied in ovarian cancer [9]. When we analyzed the clear cell renal cell carcinoma and hepatocellular carcinoma patient cohorts to evaluate the prognostic value of mRNA levels of the four genes, we found that elevated expression was significantly associated with long overall survival (Fig.…”