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British Journal of Cancer logoLink to British Journal of Cancer
. 1996 May;73(10):1193–1200. doi: 10.1038/bjc.1996.230

Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance.

J G Reeve 1, J Xiong 1, J Morgan 1, N M Bleehen 1
PMCID: PMC2074502  PMID: 8630278

Abstract

As a first step towards elucidating the potential role(s) of bcl-2 and bcl-2-related genes in lung tumorigenesis and therapeutic responsiveness, the expression of these genes has been examined in a panel of lung cancer cell lines derived from untreated and treated patients, and in cell lines selected in vitro for multidrug resistance. Bcl-2 was hyperexpressed in 15 of 16 small-cell lung cancer (SCLC) cell lines and two of five non-small-cell lung cancer (NSCLC) lines compared with normal lung and brain, and hyperexpression was not chemotherapy related. Bcl-x was hyperexpressed in the majority of SCLC and NSCLC cell lines as compared with normal tissues, and all lung tumour lines preferentially expressed bcl-x1-mRNA, the splice variant form that inhibits apoptosis. Bax gene transcripts were hyperexpressed in most SCLC and NSCLC cell lines examined compared with normal adult tissues. Mutant p53 gene expression was detected in the majority of the cell lines and no relationship between p53 gene expression and the expression of either bcl-2, bcl-x or bax was observed. No changes in bcl-2, bcl-x and bax gene expression were observed in multidrug-resistant cell lines compared with their drug-sensitive counterparts.

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Selected References

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  1. Baillie-Johnson H., Twentyman P. R., Fox N. E., Walls G. A., Workman P., Watson J. V., Johnson N., Reeve J. G., Bleehen N. M. Establishment and characterisation of cell lines from patients with lung cancer (predominantly small cell carcinoma). Br J Cancer. 1985 Oct;52(4):495–504. doi: 10.1038/bjc.1985.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ben-Ezra J. M., Kornstein M. J., Grimes M. M., Krystal G. Small cell carcinomas of the lung express the Bcl-2 protein. Am J Pathol. 1994 Nov;145(5):1036–1040. [PMC free article] [PubMed] [Google Scholar]
  3. Boise L. H., González-García M., Postema C. E., Ding L., Lindsten T., Turka L. A., Mao X., Nuñez G., Thompson C. B. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993 Aug 27;74(4):597–608. doi: 10.1016/0092-8674(93)90508-n. [DOI] [PubMed] [Google Scholar]
  4. Campos L., Rouault J. P., Sabido O., Oriol P., Roubi N., Vasselon C., Archimbaud E., Magaud J. P., Guyotat D. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993 Jun 1;81(11):3091–3096. [PubMed] [Google Scholar]
  5. Cotter F. E., Johnson P., Hall P., Pocock C., al Mahdi N., Cowell J. K., Morgan G. Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model. Oncogene. 1994 Oct;9(10):3049–3055. [PubMed] [Google Scholar]
  6. Dole M., Nuñez G., Merchant A. K., Maybaum J., Rode C. K., Bloch C. A., Castle V. P. Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. Cancer Res. 1994 Jun 15;54(12):3253–3259. [PubMed] [Google Scholar]
  7. Fisher T. C., Milner A. E., Gregory C. D., Jackman A. L., Aherne G. W., Hartley J. A., Dive C., Hickman J. A. bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res. 1993 Jul 15;53(14):3321–3326. [PubMed] [Google Scholar]
  8. Haldar S., Negrini M., Monne M., Sabbioni S., Croce C. M. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res. 1994 Apr 15;54(8):2095–2097. [PubMed] [Google Scholar]
  9. Hennet T., Bertoni G., Richter C., Peterhans E. Expression of BCL-2 protein enhances the survival of mouse fibrosarcoid cells in tumor necrosis factor-mediated cytotoxicity. Cancer Res. 1993 Mar 15;53(6):1456–1460. [PubMed] [Google Scholar]
  10. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  11. Kamesaki S., Kamesaki H., Jorgensen T. J., Tanizawa A., Pommier Y., Cossman J. bcl-2 protein inhibits etoposide-induced apoptosis through its effects on events subsequent to topoisomerase II-induced DNA strand breaks and their repair. Cancer Res. 1993 Sep 15;53(18):4251–4256. [PubMed] [Google Scholar]
  12. Lowe S. W., Ruley H. E., Jacks T., Housman D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993 Sep 24;74(6):957–967. doi: 10.1016/0092-8674(93)90719-7. [DOI] [PubMed] [Google Scholar]
  13. Lu Q. L., Elia G., Lucas S., Thomas J. A. Bcl-2 proto-oncogene expression in Epstein-Barr-virus-associated nasopharyngeal carcinoma. Int J Cancer. 1993 Jan 2;53(1):29–35. doi: 10.1002/ijc.2910530107. [DOI] [PubMed] [Google Scholar]
  14. Manome Y., Weichselbaum R. R., Kufe D. W., Fine H. A. Effect of Bcl-2 on ionizing radiation and 1-beta-D-arabinofuranosylcytosine-induced internucleosomal DNA fragmentation and cell survival in human myeloid leukemia cells. Oncol Res. 1993;5(3):139–144. [PubMed] [Google Scholar]
  15. Matlashewski G. J., Tuck S., Pim D., Lamb P., Schneider J., Crawford L. V. Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol. 1987 Feb;7(2):961–963. doi: 10.1128/mcb.7.2.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McDonnell T. J. Cell division versus cell death: a functional model of multistep neoplasia. Mol Carcinog. 1993;8(4):209–213. doi: 10.1002/mc.2940080402. [DOI] [PubMed] [Google Scholar]
  17. McDonnell T. J., Troncoso P., Brisbay S. M., Logothetis C., Chung L. W., Hsieh J. T., Tu S. M., Campbell M. L. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992 Dec 15;52(24):6940–6944. [PubMed] [Google Scholar]
  18. Miyashita T., Harigai M., Hanada M., Reed J. C. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994 Jun 15;54(12):3131–3135. [PubMed] [Google Scholar]
  19. Miyashita T., Krajewski S., Krajewska M., Wang H. G., Lin H. K., Liebermann D. A., Hoffman B., Reed J. C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994 Jun;9(6):1799–1805. [PubMed] [Google Scholar]
  20. Miyashita T., Reed J. C. Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line. Blood. 1993 Jan 1;81(1):151–157. [PubMed] [Google Scholar]
  21. Miyashita T., Reed J. C. bcl-2 gene transfer increases relative resistance of S49.1 and WEHI7.2 lymphoid cells to cell death and DNA fragmentation induced by glucocorticoids and multiple chemotherapeutic drugs. Cancer Res. 1992 Oct 1;52(19):5407–5411. [PubMed] [Google Scholar]
  22. Ohmori T., Podack E. R., Nishio K., Takahashi M., Miyahara Y., Takeda Y., Kubota N., Funayama Y., Ogasawara H., Ohira T. Apoptosis of lung cancer cells caused by some anti-cancer agents (MMC, CPT-11, ADM) is inhibited by bcl-2. Biochem Biophys Res Commun. 1993 Apr 15;192(1):30–36. doi: 10.1006/bbrc.1993.1377. [DOI] [PubMed] [Google Scholar]
  23. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  24. Pezzella F., Turley H., Kuzu I., Tungekar M. F., Dunnill M. S., Pierce C. B., Harris A., Gatter K. C., Mason D. Y. bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med. 1993 Sep 2;329(10):690–694. doi: 10.1056/NEJM199309023291003. [DOI] [PubMed] [Google Scholar]
  25. Reed J. C., Meister L., Tanaka S., Cuddy M., Yum S., Geyer C., Pleasure D. Differential expression of bcl2 protooncogene in neuroblastoma and other human tumor cell lines of neural origin. Cancer Res. 1991 Dec 15;51(24):6529–6538. [PubMed] [Google Scholar]
  26. Reeve J. G., Morgan J., Schwander J., Bleehen N. M. Role for membrane and secreted insulin-like growth factor-binding protein-2 in the regulation of insulin-like growth factor action in lung tumors. Cancer Res. 1993 Oct 1;53(19):4680–4685. [PubMed] [Google Scholar]
  27. Twentyman P. R., Fox N. E., Wright K. A., Bleehen N. M. Derivation and preliminary characterisation of adriamycin resistant lines of human lung cancer cells. Br J Cancer. 1986 Apr;53(4):529–537. doi: 10.1038/bjc.1986.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Walton M. I., Whysong D., O'Connor P. M., Hockenbery D., Korsmeyer S. J., Kohn K. W. Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res. 1993 Apr 15;53(8):1853–1861. [PubMed] [Google Scholar]
  29. Williams G. T., Smith C. A. Molecular regulation of apoptosis: genetic controls on cell death. Cell. 1993 Sep 10;74(5):777–779. doi: 10.1016/0092-8674(93)90457-2. [DOI] [PubMed] [Google Scholar]

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