Abstract
A recent study reveals that the kinase SIK2 helps ovarian cancer cells metastasize and establish themselves in the fat-rich tissues of the abdominal cavity by promoting fatty-acid metabolism and cell proliferation. Mice bearing SIK2-overexpressing human ovarian cancer cells had larger, more abundant metastases than those whose tumors bore an inactive form of the kinase.
The metabolic kinase SIK2 fosters ovarian cancer metastasis, a recent study reveals, suggesting that inhibiting this enzyme could help prevent metastases from forming.
Ovarian cancer cells usually metastasize to the omentum, a fat-rich layer in the abdomen. For patients, the main cause of death is malnutrition following intestinal blockages caused by the metastases. However, how these metastatic tumor cells establish themselves in their new environment has been unclear.
To find out, Ahmed Ahmed, MD, PhD, of Oxford University in the UK, and his colleagues followed up on one of their previous studies showing that SIK2 expression was much higher in metastases than in primary ovarian tumors. Because SIK2 regulates functions such as insulin secretion and fatty-acid metabolism, the researchers hypothesized that it encourages metastasis.
Ahmed and colleagues found that high intracellular calcium levels induced adipocytes to activate SIK2, which led to suppression of another enzyme, acetyl-CoA carboxylase, and a subsequent increase in fatty-acid oxidation. Activated SIK2 also directly stimulated PI3K/AKT signaling. The team concluded that SIK2 drives ovarian tumor metastasis by simultaneously promoting two major pathways: fatty-acid metabolism, which provides nourishment; along with cell proliferation and survival.
When they measured SIK2′s impact on metastasis, the researchers determined that mice bearing SIK2-overexpressing human ovarian cancer cells had larger, more abundant metastases than rodents whose tumors bore an inactive version of the kinase. SIK2 depletion reduced the size and number of these metastases.
“We think SIK2 plays an important role in establishing ovarian cancer metastases in the omentum and peritoneal cavity,” Ahmed says. The researchers aren't sure whether SIK2 activation occurs only after the cancer cells have moved to the omentum or also while they are in transit through the peritoneal cavity, he adds.
“This study is a provocative demonstration that SIK2 is regulating the metastatic potential of ovarian cancer cells,” agrees Elise Kohn, MD, of the NCI in Bethesda, MD, who wasn't connected to the research. “It's the beginning of a great set of opportunities scientifically, translationally, and ultimately clinically,” she says.
Ahmed notes that SIK2 inhibitors already exist. “We hope to take one or more into early-phase clinical trials soon,” he says. He envisions that patients would receive a SIK2 inhibitor after first-line treatment to prevent their ovarian tumors from metastasizing if recurrence happens. –Mitch Leslie