Functions of secreted phospholipase A2 and its interacting proteins in liposome uptake and prostate cancer progression
Quach, Nhat Dinh
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Secreted phospholipase A2 (sPLA2) are enzymes that can cleave phospholipids into lysophospholipids and fatty acids. sPLA2 are overexpressed in numerous inflammatory-related diseases including cancer. Despite many studies suggesting correlations between sPLA2 expression and severity of inflammatory-related pathologies, the role of the enzyme remains controversial, especially in cancer. The main reason can possibly be that overexpression of sPLA2 is often assumed to be correlated to an increase of lipolytic activity in previous studies. The presence of other biological entities that interact with sPLA2 and possibly post-translationally modify the enzyme can alter the activity regardless of sPLA2 expression and these biological molecules have not been taken into consideration for disease progression. Thus, the goals of this dissertation work are to (1) provide a thorough review about the PLA2 and their interacting proteins (eg. PLA2R1, GPC-1, PRMT5) in diseases and current therapeutic approaches to pharmacologically target sPLA2, (2) to experimentally determine the role of PLA2R1 in liposome uptake and prostate cancer progression, (3) to evaluate the role of GPC-1 in protecting cancer cells from Group IIA sPLA2-induced toxicity, (4) to determine the role of GPC-1 in prostate cancer cell and tumor growth, and (5) to provide evidence that PRMT5 and maybe other post-modifying proteins can target Group IIA sPLA2 and alter the lipase activity. Our data suggest that (1) overexpression of sPLA2 can be a target for drug delivery using liposomes even though the enhanced efficacy of the liposome may not be dependent on sPLA2 activity, and (2) cancer cells with high expression of GPC-1 (as a biological inhibitor) and PRMT5 (as a post-translational modifying enzyme) can alter sPLA2 activity. Our findings hopefully serve as a foundation for future studies in other diseases.