Screen for potential selective inhibitors of Rho GTPases
Date
2019
Authors
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Publisher
University of Delaware
Abstract
Inflammatory breast cancer (IBC) is arguably the most aggressive and deadly form of epithelial breast cancer. IBC is known to be a rapidly growing, distinct form of locally advanced breast cancer that is characterized by primary skin changes like edema, erythema, and peau d’orange (skin dimpling). According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, the incidence rates of IBC are significantly higher among African-American and Hispanic women in comparison to Caucasian and non-Hispanic Caucasian women. Pathologically, IBC develops tumor emboli that invade and block the dermal lymphatics of the skin over the breast. This highly metastatic disease carries a 5- and 10-year disease-free survival rates of <45% and <20%, respectively. Thus, making itcritical to develop therapeutics to combat the aggressiveness of IBC. Early work from the van Golen lab demonstrated a role for RhoC GTPase in conferring the invasive phenotype of IBC cells, where RhoC was characterized to be relatively over activated in over 90% IBC patient samples. RhoC GTPase is a member of the Ras homology- superfamily, known to act as “binary molecular switch” in signaling of many cellular processes like cytoskeletal dynamics and morphology. RhoC GTPase activity is
regulated by GEFs, GAPs, and GDIs which cycle it between a GTP-bound (“on”) state and GTP-bound (“off”) state. Subsequent work has demonstrated a role for RhoC as a driver of metastasis in multiple cancers, including melanoma. Recently, a plant extract known as Ambrosin (Amb) has been suggested to target RhoC with binding affinity for its active site. In this screening, we set out to determine whether Amb is a specific inhibitor of pro-metastatic RhoC GTPases that is elevated in aggressive cancer cells. To do this we planned to demonstrate Amb is selective for RhoC GTPases by inhibiting its activation thus over expression and then to functionally screening the effects of Ambrosin on IBC and metastatic melanoma to determine inhibition of grow/cell viability, invasiveness, and stimulation of apoptosis. Our results suggest that Ambrosin can be us to specifically target RhoC GTPases and prevent and/or inhibit metastasis. Thus, adding to the knowledge and aiding the forthcoming development of a specific RhoC therapeutic agent that would save the lives of many women affected by aggressive and invasive cancer phenotypes, like IBC and metastatic melanoma.