Expression of a peroxisome proliferator-activated receptor gamma 1 splice variant that was identified in human lung cancers suppresses cell death induced by cisplatin and oxidative stress.
OBJECTIVE
The activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 PPAR gamma1 (hPPAR gamma1) 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 hPPAR gamma1 (hPPAR gamma1(tr)) in primary human lung cancer tissues.


METHODS
The expression and localization of hPPAR gamma1(tr) was surveyed in human primary lung cancer tissues using immunohistochemistry and Western blot analysis. Using transfectants stably expressing wild-type hPPAR gamma1 (hPPAR gamma1(wt)) and hPPAR gamma1(tr), we also analyzed the pathophysiologic roles of hPPAR gamma1(tr).


RESULTS
We showed that PPAR gamma 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 PPAR gamma1(tr) in primary lung SCC tissue but not in nontumorous tissue. Expression of PPAR gamma1(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 PPAR gamma1(tr) with small interfering RNA.


CONCLUSIONS
hPPAR gamma1(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 PPAR gamma1(tr)-expressing cells may be associated with increased tumor aggressiveness and poor clinical prognosis of patients.
Kim
Hyo Jung
HJ
Department of Pharmacology, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju, Korea.
Hwang
Jin-Yong
JY
Kim
Hyun Jun
HJ
Choi
Wan Sung
WS
Lee
Jae Heun
JH
Kim
Hye Jung
HJ
Chang
Ki Churl
KC
Nishinaka
Toru
T
Yabe-Nishimura
Chihiro
C
Seo
Han Geuk
HG
D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D002945:Cisplatin