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Mechanism of FHIT-Induced Apoptosis in Lung Cancer Cell Lines  

Yoo, Jung Sun (Department of Internal Medicine and Laboratory of Experimental Therapeutics, Korea Cancer Center Hospital)
Kim, Cheol Hyeon (Department of Internal Medicine and Laboratory of Experimental Therapeutics, Korea Cancer Center Hospital)
Publication Information
Tuberculosis and Respiratory Diseases / v.56, no.5, 2004 , pp. 450-464 More about this Journal
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.
Keywords
Fragile histidine triad (FHIT); Apoptosis; Lung neoplasms; Paclitaxel; Cisplatin;
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1 Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, Gregorio LD, Pastorino U, Pierotti MA, Ohta M, Heubner K, Croce CM. The FHIT gene at 3p14.2 is abnormal in lung cancer. Cell 1996;85:17-26
2 Ishii H, Dumon KR, Vecchione A, Trapasso F, Mimori K, Alder H, Mori M, Sozzi G, Baffa R, Huebner K, Croce CM. Effect of adenoviral transduction of the fragile histi-dine triad gene into esophageal cancer cells. Cancer Res 2001;61:1578-84
3 Dumon KR, Ishii H, Vecchione A, Trapasso F, Baldassarre G, Chakrani F, Druck T, Rosato EF, Williams NN, Baffa R, During MJ, Huebner K, Croce CM. Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer. Cancer Res 2001;61:4827-36
4 Sevignani C, Calin GA, Cesari R, Sarti M, Ishii H, Yendamuri S, Vecchione A, Trapas-so F, Croce CM. Restoration of fragile histidine triad (FHIT) expression induces apoptosis and suppresses tumorigenicity in breast cancer cell lines. Cancer Res 2003;63:1183-7
5 Brauch H, Johnson B, Hovis J, Yano T,Gazdar A, Pettengill OS, Graziano S, Sore-nson GD, Poiesz BJ, Minna J, Linehan N, Zbar B. Molecular analysis of the short arm of chromosome 3 in small-cell and nonsmall-cell carcinoma of the lung. N Engl J Med 1987;317:1109-13
6 Roz L, Gramegna M, Ishii H, Croce CM, Sozzi G. Restoration of fragile histidine triad (FHIT) expression induces apoptosis and suppresses tumorigenicity in lung and cer-vical cancer cell lines. Proc Natl Acad Sci USA 2002;99:3615-20
7 Daly MC, Xiang RH, Buchhagen D, Hensel CH, Garcia DK, Killary AM, Minna JD, Naylor SL. A homozygous deletion on chro-mosome 3 in a small cell lung cancer cell line correlates with a region of tumor sup-pressor activity. Oncogene 1993;8:1721-9
8 Kok K, Hosfra R, Pilz A, van den Berg A, Terpstra P, Buys CH, Carrit B. A gene in the chromosomal region 3p21 with greatly reduced expression in lung cancer is similar to the gene for ubiquitin activation enzyme. Proc Natl Acad Sci USA 1993;90:6071-5
9 Fong KM, Biesterveld EJ, Virmani A, Wistuba I, Sekido Y, Bader SA, Ahmadian M, Ong ST, Rassool FV, Zimmerman PV, Giaccone G, Gazdar AF, Minna JD. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial le-sions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 1997;57:2256-67
10 Sozzi G, Tornielli S, Tagliabue E. Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Res 1997;57:5207-12
11 Sozzi G, Alder H, Tornielli S, Corletto V, Baffa R, Veronese ML, Negrini M, Pilotti S, Pierotti MA, Huebner K, Croce CM. Aber-rant FHIT transcripts in Merkel cell car-cinoma. Cancer Res 1996;56:2472-4
12 Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, Rabbitts P. p53 and chromosome 3 abnormalities, characteristic of malignant lung tumors, are detectable in preinvasive lesions of the bronchus. Onco-gene 1992;7:1989-97
13 Virgilio L, Shuster M, Gollin SM, Veronese ML, Ohta M, Huebner K, Croce CM. FHIT gene alterations in head and neck squamous cell carcinomas. Proc Natl Acad Sci USA 1996;93:9770-5
14 Killary AM, Wolf ME, Giambernardi TA, Naylor SL. Definition of a tumor suppressor locus within human chromosome 3p21-p22. Proc Natl Acad Sci USA 1992;89:10877-81
15 Askari MD, Vo-Dinh T. Implication of mito-chondrial involvement in apoptotic activity of fragile histidine triad gene: application of synchronous luminescence spectroscopy. Bio-polymers 2004;73:510-23
16 Sard L, Accornero P, Tornielli S, Delia D, Bunone G, Campiglio M, Colombo MP, Gramegna M, Croce CM. The tumor-sup-pressor gene FHIT is involved in the regula-tion of apoptosis and in cell cycle control. Proc Natl Acad Sci USA 1999;96:8489-92
17 Smeets DF, Scheres JM, Hustinx TW. The most common fragile site in man is 3p14. Hum Genet 1986;72:215-20
18 Kastury K, Baffa R, Druck T, Ohta M, Cotticelli MG, Inoue H, Negrini M, Rugge M, Huang D, Croce CM, Palazzo J, Huebner K. Potential gastrointestinal tumor suppressor locus at the 3p14.2 FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res 1996;56:978-83
19 Negrini M, Monaco C, Vorechovsky I, Ohta M, Druck T, Baffa R, Huebner K, Croce CM. The FHIT gene at 3p14.2 is abnormal in breast carcinomas. Cancer Res 1996;56:3173-9
20 Yanagisawa K, Kondo M, Osada H, Uchida K, Takagi K, Masuda A, Takahashi T, Taka-hashi T. Molecular analysis of the FHIT gene at 3p14.2 in lung cancer cell lines. Cancer Res 1996;56:5579-82
21 Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA. Induction of apoptosis and inhi-bition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histi-dine triad (FHIT) gene overexpression. Can-cer Res 1999;59:3333-9
22 Huang Y, Garrison PN, Barnes LD. Cloning of the Schizosaccharomyces pombe gene encoding diadenosine $5-tetrapho-sphate $(A_{P4}A)$ asymmetrical hydrolase: seque-nce similarity with histidine triad (HIT) family. Biochem J 1995;312:925-32
23 Barnes LD, Garrison PN, Siprashvili Z, Gura-nowski A, Robinson AK, Ingram SW, Croce CM, Otha M, Huebner K. Fhit, a putative tumor suppressor in humans, is a dinu-cleoside 5', 5'''-P1,P3 triphosphate hydrolase. Biochemistry 1996;35:11529-35
24 Naylor SL, Johnson BE, Minna JD, Saka-guchi AY. Loss of heterozygosity of chro-mosome 3p markers in small-cell lung cancer. Nature(London) 1987;329:451-4
25 Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Heubner K. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associatedt(3;8)breakpoint, is abnormal in digestive tract cancers. Cell 1996;84:587-97
26 Yokota J, Wada M, Shimosato Y, Terada M, Sugimura T. Loss of heterozygosity on chro-mosome 3, 13, 17 in small cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci USA 1987;84:9252-6
27 Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, Suyama M, Takagi H, Nakamura Y, Takahashi T. Three distinct regions involved in 3p deletions in human lung cancer. Oncogene 1992;7:445-9
28 Hung J, Kishimoto Y, Sugio K, Virmani A, McIntire DD, Minna JD, Gazdar AF. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. J Am Med Assoc 1995;273:558-63
29 Sekido Y, Bader S, Latif F, Gnarra JR, Gadzar AF, Linehan M, Zbar B, Lerman MI, Minna JD. Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 1994;9:1599-604