Abstract
Retinoids have shown promise in cancer prevention and therapy. As some retinoids exhibit undesirable side effects, new retinoid analogs have been synthesized. In this study, we examined the effects of the retinoid MX3350-1 on human head and neck squamous cell carcinoma (HNSCC) cell lines. MX3350-1 suppressed the growth of 7/8 HNSCC cell lines by >65%. This inhibition appeared to be due to induction of apoptosis as revealed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Studies with cell line UMSCC17B indicated that apoptosis was induced within 1–2 days and involved activation of caspase-8, -9, and -3. Inhibitors of these caspases suppressed MX3350-1-induced apoptosis. MX3350-1 decreased the levels of antiapoptotic Bcl-2 and Bcl-XL, increased proapoptotic Bax, induced mitochondrial membrane permeabilization (MMP), and cytochrome c release from mitochondria to cytosol. The antioxidant butylated hydroxyanisol and the MMP inhibitor cyclosporin A (Cs A) blocked apoptosis induced by MX3350-1. In contrast, retinoid receptor antagonists failed to inhibit apoptosis. MX3350-1 increased the levels of Fas-ligand, Fas, and Fas-associated death domain, and enhanced activation of procaspase-8 and cleavage of its substrate Bid. Soluble Fas rescued the cells from MX3350-1-induced apoptosis. These results demonstrate that MX3350-1 induces apoptosis by activating both extrinsic and intrinsic apoptosis pathways and suggest that further studies on the potential of this retinoid for prevention and therapy of HNSCCs are warranted.
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Abbreviations
- RA:
-
retinoic acid
- HNSCC:
-
head and neck squamous cell carcinoma
- RAR:
-
retinoic acid receptor
- RXR:
-
retinoid X receptor
- SRB:
-
sulforhodamine B
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- MMP:
-
mitochondrial membrane permeabilization
- BHA:
-
butylated hydroxyanisol
- Cs A:
-
cyclosporin A
- DiOC6:
-
3′-dihexyoxacarbocyanine iodide
- CCCP:
-
carbonyl cyanide m-chlorophenylhydrazone
- FasL:
-
Fas ligand
- FADD:
-
Fas-associated death domain
- sFas:
-
soluble Fas
- MKP-1:
-
mitogen-activated protein kinase phosphatase-1
References
Bang S, Jeong EJ, Kim IK, Jung YK and Kim KS . (2000). J. Biol. Chem., 275, 36217–36222.
Bayon Y, Ortiz MA, Lopez-Hermandes FJ, Gao F, Karin M, Pfahl M and Piedrafita FJ . (2003). Mol. Cell. Biol., 23, 1061–1074.
Cao X, Deng X and May WS . (2003). Blood, 102, 2605–2614.
Chakravarti N, Mathur M, Bahadur S, Shukla NK, Rochette-Egly C and Ralhan R . (2003). Int. J. Cancer, 91, 27–31.
Chun K-H, Benbrook DM, Berlin KD, Hong WK and Lotan R . (2003a). Cancer Res., 63, 3826–3832.
Chun K-H, Lee H-Y, Hassan K, Khuri F, Hong WK and Lotan R . (2003b). Cancer Res., 63, 4796–4800.
D’Ambrosio SM, Gibson-D’Ambrosio R, Milo GE, Casto B, Kelloff GJ and Steele VE . (2001). Anticancer Res., 20, 2273–2280.
Daniel PT, Schulze-Osthoff K, Belka C and Guner D . (2003). Essays Biochem., 39, 73–88.
Disepio D, Sutter M, Johnson AT, Chandraratna RA and Nagpal S . (1999). Mol. Cell. Biol. Res. Commun., 1, 7–13.
Dragovich T, Rudin CM and Thompson CB . (1998). Oncogene, 17, 3207–3213.
Garattini E, Gianni M and Terao M . (2004). Curr. Pharm. Des., 10, 433–448.
Gross A, McDonnell JM and Korsmeyer SJ . (1999). Gene Dev., 13, 1899–1911.
Guruswamy S, Lightfoot S, Gold MA, Hassan R, Berlin KD, Ivey RT and Benbrook DM . (2001). J. Natl. Cancer Inst., 93, 516–525.
Hsu CK, Rishi AK, Li XS, Dawson MI, Reichert U, Shroot B and Fontana JA . (1997). Exp. Cell. Res., 232, 7–24.
Krilleke D, Ucur E, Pulte D, Schulze-Osthoff K, Debatin KM and Herr I . (2003). Int. J. Cancer, 107, 520–527.
Kroemer G . (1997). Nat. Med., 3, 614–620.
Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, Benner SE, Xu XC, Lee JS, Papadimitrakopoulou VM, Geyer C, Perez C, Martin JW, El-Naggar AK and Lippman SM . (2000). Clin. Cancer Res., 6, 1702–1710.
Lippman SM and Lotan R . (2000). J. Nutr., 130, 479S–482S.
Lotan R . (2001). Anticancer Res., 16, 2415–2419.
Lotan R . (2003). J. Biol. Regul. Homeost. Agents, 17, 13–28.
Lotan R, Dawson MI, Zou CC, Jong L, Lotan D and Zou CP . (1995). Cancer Res., 55, 232–236.
Lu XP, Fanjul A, Picard N, Pfahl M, Rungta D, Nared-Hood K, Carter B, Piedrafita J, Tang S, Fabbrizio E and Pfahl M . (1997). Nat. Med., 3, 686–689.
Marchetti P, Zamzami N, Joseph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G and Formstecher P . (1999). Cancer Res., 59, 6257–6266.
Mologni L, Ponzanelli I, Bresciani F, Sardiello G, Bergamaschi D, Gianni M, Reichert U, Rambaldi A, Terao M and Garattini E . (1999). Blood, 93, 1045–1061.
Nagata S and Golstein P . (1995). Science, 297, 1449–1456.
Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA and Davies PJ . (1995). Mol. Cell. Biol., 15, 3540–3551.
Ortiz MA, Lopez-Hermandes FJ, Bayon Y, Pfahl M and Piedrafita FJ . (2001). Cancer Res., 61, 8504–8512.
Pfahl M and Piedrafita FJ . (2003). Oncogene, 22, 9058–9062.
Schmitz I, Kirchhoff S and Krammer P . (2000). Int. J. Biochem. Cell. Biol., 32, 1123–1136.
Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q and Tang H . (2003). Biochem. Biophys. Res. Commun., 305, 989–996.
Shimizu S, Narita M and Tsujimoto Y . (1999). Nature, 399, 483–487.
Strasser A and Newton K . (1999). Int. J. Biochem. Cell. Biol., 31, 533–537.
Sun SY, Yue P, Chandraratna RA, Tesfaigzi Y, Hong WK and Lotan R . (2000). Mol. Pharmacol., 58, 508–514.
Sun SY, Yue P, Hong WK and Lotan R . (2000a). Cancer Res., 60, 6537–6543.
Sun SY, Yue P, Mao L, Dawson MI, Shroot B, Lamph WW, Heyman RA, Chandraratna RA, Shudo K, Hong WK and Lotan R . (2000b). Clin. Cancer Res., 6, 1563–1573.
Sun SY, Yue P, Wu GS, El-Deiry WS, Shroot B, Hong WK and Lotan R . (1999). Oncogene, 18, 2357–2365.
Tang D, Lahti JM and Kidd VJ . (2000). J. Biol. Chem., 275, 9303–9307.
Ulukaya E and Wood EJ . (1999). Cancer Treat. Rev., 25, 229–235.
Yanase N, Ohshima K, Ikegami H and Mizuguchi J . (2000). J. Interferon Cytokine Res., 20, 1121–1129.
Yin XM . (2000). Cell Res., 10, 161–167.
Acknowledgements
This study was supported in part by USPHS Head and Neck Cancer SPORE Grant P50 CA907007 and P30 CA16672-30 from the NCI.
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Chun, KH., Pfahl, M. & Lotan, R. Induction of apoptosis by the synthetic retinoid MX3350-1 through extrinsic and intrinsic pathways in head and neck squamous carcinoma cells. Oncogene 24, 3669–3677 (2005). https://doi.org/10.1038/sj.onc.1208339
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DOI: https://doi.org/10.1038/sj.onc.1208339
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