Title: Title: Deciphering phospholipid-based signaling mechanisms for lung cancer intervention

Abstract:

Lung cancer is a highly aggressive and difficult to treat human malignancy with poor prognosis. The development of tumor resistance mechanisms to the known therapeutic options pose major challenges in the treatment of lung cancer, and this provides the impetus for the intervention of new approaches. Among various cellular pathways, the phospholipid mediator, platelet-activator factor (PAF) and PAF-receptor (PAF-R) signaling plays critical roles in tumor development and metastasis as well as limiting the efficacy of therapeutic agents via immune and non-immune mechanisms. Studies, including ours, have demonstrated that exposure to pro-oxidative stressors including both environmental and therapeutic agents produce oxidized PAF and PAF-like ligands non- enzymatically via their ability to generate reactive oxygen species (ROS). Importantly, our previous studies have shown that exposure to cigarette smoke (CS) generates PAF-ligands in a PAF-R- dependent manner via mechanisms involving the induction of cyclooxygenase type 2 (COX-2) and regulatory T cells (Tregs). This CS-mediated PAF- R-ligands generation induced systemic immunosuppression in mice expressing PAF-R (WT), but not in PAF-R-deficient (Ptafr-/-) mice. This CS-induced PAF-ligands generation and systemic immunosuppression were mimicked by a known PAF-R-agonist, CPAF. Notably, the generation of PAF-ligands and induction of systemic immunosuppression were blocked by the supplementation of antioxidants, COX-2 inhibitors, PAF-metabolizing, PAF-acetyl hydrolase (PAF-AH) enzyme and depleting antibodies against Tregs, indicating the role of the PAF-R and its downstream effectors in mediating CS-induced effects. As cigarette smoking remains one of the major risk factors for lung carcinogenesis, we hypothesized that the activation of the host-PAF-R that mediates systemic immunosuppression can also modulate the growth of lung cancer in a murine experimental model. To that end, our next studies utilizing WT and Ptafr-/- mice tested if systemic CPAF treatment, which mimicked CS-induced effects, can augment the growth of murine Lewis lung carcinoma (LLC1) cells. We demonstrated that pretreatment of CPAF augmented the growth and metastatic ability of LLC1 tumors in a PAF-R- dependent manner. Analysis of the PAF-R mRNA expression revealed that LLC1 tumor cells lack functional PAF-R expression. This finding was confirmed by the analysis of cell proliferation demonstrating that CPAF failed to induce increased in vitro proliferation of LLC1 tumor cells. While detailed mechanistic studies are warranted, these data indicated that the activation of the host-PAF-R plays an important role in lung cancer development and thus, targeting PAF-R- mediated pathway could be explored as a promising approach for the intervention of lung cancer.

Biography:

Ravi P. Sahu has completed his Ph.D. from Sanjay Gandhi Post Graduate Institute of Medical Sciences and postdoctoral studies from the University of Pittsburgh Medical Center, Texas Tech University Health Science Center and Indiana University School of Medicine. He is currently an Assistant Professor at the Department of Pharmacology and Toxicology at Wright State University Boonshoft School of Medicine at Dayton, OH. He has published over 50 papers in reputed scientific journals and has been serving as an editorial board member and Adhoc reviewer of several journals.