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Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells

Oncogene volume 18, pages 2357–2365 (1999)Cite this article

Abstract

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.

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References

  • Adachi H, Preston G, Harvat B, Dawson MI and Jetten A. . 1998 Am. J. Respir. Cell Mol. 18: 823–333.

  • Benner SE, Lippman SM and Hong WK. . 1995 Oncology 9: 205–210.

  • Bernard BA, Bernardon J-M, Delescluse C, Martin B, Lenoir M-C, Margnan J, Charpentier B, Pilgrim WR, Reichert U and Shroot B. . 1992 Biochem. Biophys. Res. Commun. 186: 977–983.

  • Chambon P. . 1996 FASEB J. 10: 945–954.

  • Chen YQ, Cipriano SC, Arenkiel JM and Miller FR. . 1995 Cancer Res. 55: 4536–4539.

  • DeLuca LM. . 1991 FASEB J. 5: 2924–2933.

  • El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman GG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 1169–1174.

  • Fan S, El-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ, Magrath I, Kohn KW and O'Connor PM. . 1994 Cancer Res. 54: 5824–5830.

  • Geradts J, Chen J-Y, Russell EK, Yankaskas JR, Nieves L and Minna JD. . 1993 Cell. Growth Differ. 4: 799–809.

  • Gomez-Manzano C, Fueyo J, Kyritsis AP, McDonnell TJ, Steck PA, Levin VA and Yung WKA. . 1997 J. Natl. Cancer Inst. 89: 1036–1044.

  • Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 805–816.

  • Hsu CA, Rishi AK, Li X-S, Gerald TM, Dawson MI, Schiffer C, Reichert U, Shroot B, Poirer GC and Fontana JA. . 1997 Blood 89: 4470–4479.

  • Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE and Oltvai ZN. . 1993 Semin. Cancer Biol. 4: 327–332.

  • Landis SH, Murray T, Bolden S and Wingo PA. . 1998 CA Cancer J. Clin. 48: 6–29.

  • Lee JM and Bernstein A. . 1993 Proc. Natl. Acad. Sci. USA 90: 5742–5746.

  • Lehmann JM, Dawson MI, Hobbs PD, Husmann M and Pfahl M. . 1991 Cancer Res. 51: 4804–4809.

  • Li Y, Lin B, Agadir A, Liu R, Dawson MI, Reed JC, Fontana JA, Bost F, Hobbs PD, Zheng Y, Chen GQ, Shroot B, Mercola D and Zhang XK. . 1998 Mol. Cell. Biol. 18: 4719–4731.

  • Liebermann DA, Hoffman B and Steinman RA. . 1995 Oncogene 11: 199–210.

  • Lotan R. . 1995 J. Natl. Cancer Inst. 87: 1655–1657.

  • Lowe SW, Reuley HE, Jacks T and Housman DE. . 1993 Cell 74: 957–967.

  • Lu S, Chin KV, Saydak M, Gentile V and Davies PJ. . 1994 Proc. Am. Assoc. Cancer Res. 35: A1517.

  • Martin SJ and Green DR. . 1995 Crit. Rev. Oncol. Hematol. 18: 137–153.

  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE and Givol D. . 1994 Cancer Res. 54: 3391–3395.

  • Mitsudomi T, Steinberg SM, Nau MM, Carbone D, D'Amico D, Bodner S, Oie HK, Linnoila I, Mulshine JL, Minna JD and Gazdar AF. . 1992 Oncogene 7: 171–180.

  • Miyashita T and Reed JC. . 1995 Cell 80: 293–299.

  • Nagy L, Thomazy VA, Heyman RA and Davies PJ. . 1998 Cell Death and Differ. 5: 11–19.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ. . 1993 Cell 74: 609–619.

  • Oridate N, Higuchi M, Suzuki S, Shroot B, Hong WK and Lotan R. . 1997 Int. J. Cancer 70: 484–487.

  • Patel T, Gores GJ and Kaufmann SH. . 1996 FASEB J. 10: 587–597.

  • Piedrafita FJ and Pfahl M. . 1997 Mol. Cell. Biol. 17: 6348–6358.

  • Polyak K, Waldman T, He T-C, Kinzler KW and Vogelstein B. . 1996 Genes Dev. 10: 1945–1952.

  • Shao Z-M, Dawson MI, Li XS, Rishi AK, Sheikh MS, Han Q-X, Ordonez JV, Shroot B and Fontana JA. . 1995 Oncogene 11: 493–504.

  • Schadendorf D, Kern MA, Artuc M, Pahl HL, Rosenbach T, Fichtner I, Nurnberg W, Stuting S, Stebut EV, Worm M, Makki A, Jurgovsky K, Kolde G and Henz BM. . 1996 J. Cell. Biol. 135: 1889–1898.

  • Sheikh MS, Li X-S, Chen J-C, Shao Z-M, Ordonez JV and Fontana JA. . 1994 Oncogene 9: 3407–3415.

  • Shimanmura A and Fisher DE. . 1996 Clin. Cancer Res. 2: 435–440.

  • Sun S-Y, Yue P, Shroot B, Hong WK and Lotan R. . 1997a J. Cell. Physiol. 173: 279–284.

  • Sun S-Y, Yue P, Shroot B, Michel S, Dawson MI, Lamph WW, Heyman RA, Teng M, Chandraratna RAS, Shudo K, Hong WK and Lotan R. . 1997b Cancer Res. 57: 4931–4939.

  • Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan D-D, Zhou J-Y, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G and El-Deiry WS. . 1997 Nat. Genet. 17: 141–143.

  • Zou CP, Kurie JM, Lotan D, Zou CC, Hong WK and Lotan R. . 1998 Clin. Cancer Res. 4: 1345–1355.

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Acknowledgements

This work was supported by United States Public Health Service Grant U19 CA68437 from National Institutes of Health. WKH is an American Cancer Society Clinical Research Professor.

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  1. Shi-Yong Sun

    Present address: Department of Thoracic/Head and Neck Medical Oncology, Box 108, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas, 77030, USA

Authors and Affiliations

  1. Department of Clinical Cancer Prevention, The University of Texas, MD Anderson Cancer Center, Houston, 77030, TX, USA

    Shi-Yong Sun

  2. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, 77030, TX, USA

    Ping Yue, Waun K Hong & Reuben Lotan

  3. Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA

    Gen Sheng Wu & Wafik S El-Deiry

  4. Galderma Research and Development, Sophia Antipolis, France

    Braham Shroot

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Sun, SY., Yue, P., Wu, G. et al. Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells. Oncogene 18, 2357–2365 (1999). https://doi.org/10.1038/sj.onc.1202543

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