Shujuan Liu

Ovarian cancer-derived TGF-β1 induces cancer-associated adipocytes formation by activating SMAD3/TRIB3 pathway to establish pre-metastatic niche

AbstractOvarian cancer (OC) is prone to adipose tissue metastasis. However, the underlying molecular mechanisms remain elusive. Here, we observed that omental adipocytes were induced into cancer-associated adipocytes (CAAs) by OC-derived TGF-β1 to establish a pre-metastatic niche (PMN) through collagen and fibronectin secretion. Mechanistically, OC-derived TGF-β1 binds to adipocyte membrane receptors and thus activates intracellular signaling by SMAD3 phosphorylation. The activation of TGF-β1/SMAD3 signaling pathway dedifferentiates adipocytes into CAAs by upregulating Tribbles homolog 3 (TRIB3), which suppresses the phosphorylation of CEBPβ. Additionally, CAAs secrete collagen I, collagen VI, and fibronectin to remodel the extracellular matrix and promote the adhesion of OC cells. Pharmacological inhibition of the TGF-β1/SMAD3 pathway significantly inhibits CAAs and PMN formation, thereby reducing the OC metastatic burden. Our findings indicate that the formation of CAAs and PMN in adipose tissues facilitates OC cell implantation and blocking the TGF-β1/SMAD3 signaling pathway could prevent OC omental metastasis.

SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer

Salt-inducible kinase 2 (SIK2), which belongs to the AMP-activated protein kinase family, modulates various biological functions including fatty acid oxidation. However, the role of SIK2 in glucose metabolism reprogramming remains unclear in ovarian cancer (OC) cells. Here, we found that SIK2 significantly enhanced the Warburg effect of OC cells mainly through two mechanisms. On the one hand, SIK2 upregulated the expression of HIF-1α by activating the PI3K/AKT signaling pathway, which directly upregulated the transcription of major glycolytic genes to promote glycolysis. On the other hand, SIK2 promoted mitochondrial fission through phosphorylation of Drp1 at Ser616 site, which inhibited the mitochondrial oxidative phosphorylation. In addition, SIK2 promoted growth and metastasis of OC cells by promoting cell proliferation and inhibiting cell apoptosis, as well as enhancing the epithelial-mesenchymal transition. Moreover, the SIK2-mediated reprogramming of glucose metabolism played a critical role in growth and metastasis of OC cells. Collectively, our findings demonstrate that SIK2 is a crucial regulator of glucose metabolism in OC cells through activation of PI3K/AKT/HIF-1α pathway and Drp1 phosphorylation-mediated mitochondrial fission, which plays a critical oncogenic role in OC cells.