Oxidized lipids in radiation therapy mediated acquired resistance of melanoma

Abstract

Our previous studies have established that pro‐oxidative stressors including UVB and chemotherapeutic agents generate oxidized lipids, glycerophosphocholines (Ox‐GPCs) that act as potent platelet‐activating factor‐receptor (PAF‐R) agonists and inhibit host anti‐tumor immunity. Since X‐ray radiation therapy (XRT) act as a potent pro‐oxidative stressor, the present studies investigated if XRT could thwart melanoma anti‐tumor immunity via PAF‐R activation. We demonstrate that treatment of in‐vitro melanoma and normal keratinocyte cells with XRT generates PAF‐R‐agonists only by melanoma cells in a dose and time dependent manner as measured by functional Ca2+ mobilization assay using retrovirally generated PAF‐R expressing and deficient epidermal cells. Antioxidants, vitamin C or N‐acetyl cysteine partially blocked IR mediated Ox‐GPCs production, indicating that XRT generates PAF‐R agonists via both enzymatic and non‐enzymatic pathways. Additionally, localized XRT of melanoma tumors grown on syngeneic mice resulted in PAF‐R agonists production. In a dual tumor model, we show that XRT of one tumor significantly augments the growth of other (untreated) tumor in a PAF‐R‐dependent manner. Moreover, XRT‐mediated PAF‐R‐dependent increased tumor growth was blocked by systemic cyclooxygenase‐2 (COX‐2) inhibitors. Furthermore, we detected several novel Ox‐GPCs with significantly increased PAF species in XRT‐treated melanoma cells compared to sham‐treated cells. These findings explain some instances of XRT treatment failure and provide novel therapeutic target by which PAF‐R agonists produced via XRT modulate tumor growth via PAF‐R‐COX‐2‐dependent pathway.