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Expression of a Peroxisome Proliferator-Activated Receptor 1 Splice Variant that Was Identified in Human Lung Cancers Suppresses Cell Death Induced by Cisplatin and Oxidative Stress

Authors' Affiliations: Departments of ¹ Pharmacology, ² Internal Medicine, and ³ Anatomy, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju, Korea and ⁴ Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Requests for reprints: Han Geuk Seo, Department of Pharmacology, College of Medicine, Gyeongsang National University, 92 Chilam-Dong, Jinju 660-751, Korea. Phone: 82-55-751-8773; Fax: 82-55-759-0609; E-mail: hgseo{at}gnu.ac.kr.

Purpose: The activation of peroxisome proliferator-activated receptor (PPAR) has been implicated in the inhibition of tumor progression in lung cancers through the induction of differentiation and apoptosis. Recently, we identified a novel splice variant of human PPAR1 (hPPAR1) that exhibits dominant-negative activity in human tumor-derived cell lines. This study aimed to examine the expression and pathophysiologic roles of a truncated splice variant of hPPAR1 (hPPAR1_tr) in primary human lung cancer tissues.

Experimental Design: The expression and localization of hPPAR1_tr was surveyed in human primary lung cancer tissues using immunohistochemistry and Western blot analysis. Using transfectants stably expressing wild-type hPPAR1 (hPPAR1_wt) and hPPAR1_tr, we also analyzed the pathophysiologic roles of hPPAR1_tr.

Results: We showed that PPAR is expressed predominantly in the nucleus of nontumorous tissues, whereas it is present in both the nucleus and the cytoplasm of tumorous tissues in squamous cell carcinoma (SCC) of the lung. Western blot analysis confirmed the presence of PPAR1_tr in primary lung SCC tissue but not in nontumorous tissue. Expression of PPAR1_tr in Chinese hamster ovary cells attenuated their susceptibility to cell death induced by oxidative stress or cisplatin, whereas their susceptibility was completely recovered by down-regulation of PPAR1_tr with small interfering RNA.

Conclusions: hPPAR1_tr is expressed strongly in tumorous tissues of primary human lung SCC and its overexpression renders transfected cells more resistant to chemotherapeutic drug- and chemical-induced cell death. These data suggest that the decreased drug sensitivity of PPAR1_tr-expressing cells may be associated with increased tumor aggressiveness and poor clinical prognosis of patients.