A Novel Role of Dlc2 in Regulating Macropinocytosis Through the Cdc42/Rac Pathway in Ovarian Cancer Cells

Abstract

Ovarian carcinoma is eighth most common leading cause of death among all mortality causes globally. It is among the most common gynecological cancers. Diagnosis of this type of cancer is very challenging due to frequently uncommon symptoms. The prognosis of lately diagnosed ovarian cancer is very poor with a 10-year survival rate of 40% to 50%. Several mutations affecting fundamental cell processes such as proliferation and metastasis lead to the development of this type of cancer. This is specifically mediated by Rho GTPases, their regulators, and downstream targets which lead to the development of ovarian cancer. Our lab is involved in examining the signaling pathways leading to this disease. DLC2 is a protein that has been identified to act as a tumor suppressor in some cancer types such as hepatocellular carcinoma where it has been downregulated. It has also been implicated in carcinogenesis by acting as a Rho GAP for some Rho GTPases such as Cdc42. In this study, we aimed to demonstrate the role of DLC2 in ovarian cancer cells, identify the crosstalk between DLC2 and Rho GTPases, while studying the role of DLC2 in regulating Macropinocytosis. We used a DLC2 knockdown model to study the effect of this protein on cell morphology and on Cdc42 in SKOV3 and Caov-3 cell lines. The results show that StarD13 knockdown leads to a ruffle phenotype by acting as a GAP for Cdc42, relieving the inhibitory effect on this Rho GTPase. We have also determined a novel role of DLC2 in inhibiting the process of macropinocytosis via the Cdc42/Rac1 pathway. As such, we have been able to characterize a potential crosstalk between DLC2 and Rho GTPases on this unselective feeding mechanism of macropinocytosis.