Mechanism of FHIT-Induced Apoptosis in Lung Cancer Cell Lines.

Yoo, Jung Sun; Kim, Cheol Hyeon

doi:2004.56.5.450

Tuberc Respir Dis > Volume 56(5); 2004 > Article

Original Article

Tuberculosis and Respiratory Diseases 2004;56(5):450-464.
DOI: https://doi.org/10.4046/trd.2004.56.5.450 Published online May 1, 2004.

Mechanism of FHIT-Induced Apoptosis in Lung Cancer Cell Lines.

Jung Sun Yoo, Cheol Hyeon Kim

Department of Internal Medicine and Laboratory of Experimental Therapeutics, Korea Cancer Center Hospital, Korea. cheol@kcch.re.kr

Abstract

BACKGROUND
The FHIT (fragile histidine triad) gene is a frequent target of deletions associated with abnormal RNA and protein expression in lung cancer. Previous studies have shown FHIT gene transfer into lung cancer cell line lacking FHIT protein expression resulted in inhibition of tumor cell growth attributable to the induction of apoptosis and reversion of tumorigenecity. However, the mechanism of the tumor suppressor activity of the FHIT gene and the cellular pathways associated with its function are not completely understood. METHODS: To gain insight into the biological function of FHIT, we compared the NCI-H358 cell line with its stable FHIT transfectants after treatment with cisplatin or paclitaxel. We investigated the effects of FHIT gene expression on cell proliferation, apoptosis, and activation of caspase system and Bcl-2 family. The induction of apoptosis was evaluated by using DAPI staining and flow cytometry. Activation of caspases and Bcl-2 members was evaluated by Western blot analysis. RESULTS: A significantly increased cell death was observed in FHIT transfectants after cisplatin or paclitaxel treatment and this was attributable to the induction of apoptosis. Remarkable changes in caspases and Bcl-2 family were observed in the transfected cells as compared with the control cells after treatment with paclitaxel. Activation of caspase-3 and caspase-7 was markedly increased in cells expressing FHIT. Expression level of Bcl-2 and Bcl-xL protein was significantly decreased and that of Bax and Bad protein was significantly increased in the transfected cells. CONCLUSION: FHIT gene delivery into lung cancer cells results in enhanced apoptosis induced by treatment with cisplatin or paclitaxel. The data suggest that apoptosis in FHIT-expressing cells could be related to activation of caspase pathway and Bcl-2 family.

Key Words: Fragile histidine triad (FHIT), Apoptosis, Lung neoplasms, Paclitaxel, Cisplatin

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