THE IMPORTANCE OF THE ACYLTRANSFERASE LYCAT ON PI3K-AKT SIGNALING AND CANCER CELL PROLIFERATION

Candidate: Victoria Chan
Supervisor: Dr. Roberto Botelho and Dr. Costin Antonescu

Abstract:

Phosphoinositides (PIPs) play a key role in signaling and regulating cellular functions. PIPs are enriched with a unique acyl chain profile composed of stearate and arachidonate at the sn-1 and sn-2 positions, respectively; the combination of which is referred to as C38:4. This acyl specificity is governed by phospholipase As (PLAs) and acyltransferases. Specifically, lysocardiolipin acyltransferase (LYCAT) is responsible for incorporating stearic acid onto the sn-1 position of PIPs.

Previous work has shown that LYCAT silencing selectively perturbs the levels and localization of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). PI(4,5)P2 is an important precursor lipid to phosphatidylinositol-3,4,5-trisphosphate (PIP3), which recruits and modulates effectors such as the kinase Akt, promoting and coordinating processes such as cell survival and proliferation.

Thus, we hypothesized that LYCAT is important in PIP3-Akt signaling, cell proliferation and apoptosis. Our results show that LYCAT silencing suppresses epidermal growth factor (EGF) stimulated Akt phosphorylation, as well as the phosphorylation of key substrates downstream of Akt, such as TSC2 and GSK3.. At the cellular level, we observed a decrease in cell proliferation and an increase in cytotoxicity upon LYCAT silencing. Overall, our research suggests that the acyl specificity governed by LYCAT may play a significant role in controlling cell signaling and proliferation, which may have consequences for diseases such as cancer.