Abstract
N-(4-hydroxyphenyl)retinamide (4-HPR, fenretinide) is a potent chemopreventive agent whose effect has been suggested to involve apoptosis induction. 4-HPR induces a loss of the mitochondrial transmembrane potential and the mitochondrial release of cytochrome c before caspase activation. Inhibition of mitochondrial membrane permeabilization (MMP) by transfection with Bcl-2 or the Cytomegalovirus UL37 gene product vMIA prevented caspase activation and cell death. In contrast to other retinoid derivatives, 4-HPR has no direct MMP-inducing effects when added to isolated mitochondria or when added to proteoliposomes containing the MMP-regulatory permeability transition pore complex (PTPC). Moreover, although reactive oxygen species (ROS) overproduction appears to be instrumental for 4-HPR-induced MMP and apoptosis, inhibition of the NF-κB or p53-mediated signal transduction pathways failed to modulate 4-HPR-induced apoptosis. 4-HPR was found to cause an antioxidant-inhibitable conformational change of both Bax and Bak, leading to the exposure of their N-termini and to the mitochondrial relocalization of Bax. Cells with a Bax−/− Bak−/− genotype were resistant against the 4-HPR-induced MMP, overproduction of ROS and cell death. Altogether, these data indicate that 4-HPR induces MMP through an ROS-mediated pathway that involves the obligatory contribution of the proapopotic Bcl-2 family members Bax and/or Bak.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- 4-HPR:
-
4-hydroxyphenylretinamide
- ANT:
-
adenine nucleotide translocator
- Asp2R110:
-
rhodamine 110-Asp2
- Atr:
-
atractyloside
- atRA:
-
all-trans-retinoic acid
- Casp-3a:
-
activated caspase-3
- CMXRos:
-
chloromethyl-X-rosamine
- Cyt c:
-
cytochrome c
- ΔΨm:
-
mitochondrial transmembrane potential
- DAPI:
-
4′,6-diamidino-2-phenylindole,dihydrochloride
- DiOC6(3):
-
3,3′dihexyloxacarbocyanine iodide
- Eth:
-
ethidium
- HE:
-
hydroethidine
- MMP:
-
mitochondrial membrane permeabilization
- 4-MU:
-
4-methylumbelliferone
- 4-MUP∣4-methylumbelliferylphosphate∣PTPC:
-
permeability transition pore complex
- PI:
-
propidium iodide
- ROS:
-
reactive oxygen species
- vMIA:
-
viral mitochondrial inhibitor of apoptosis
- Z-VAD.fmk:
-
N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
References
Appierto V, Cavadini E, Pergolizzi R, Cleris L, Lotan R, Canevari S and Formelli F . (2001). Br. J. Cancer, 84, 1528–1534.
Asumendi A, Morales MC, Alvarez A, Arechaga J and Perez-Yarza G . (2002). Br. J. Cancer, 86, 1951–1956.
Belzacq AS, El Hamel C, Vieira HLA, Cohen I, Haouzi D, Metivier D, Marchetti P, Goldmacher V, Brenner C and Kroemer G . (2001). Oncogene, 20, 7579–7587.
Brenner C, Marzo I, de Araujo Vieira HL and Kroemer G . (2000). Methods Enzymol., 322, 243–252.
Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW and Vogelstein B . (1999). J. Clin. Invest., 104, 263–269.
Cai J and Jones DP . (1998). J. Biol. Chem., 273, 11401–11404.
Castedo M, Ferri K, Roumier T, Metivier D, Zamzami N and Kroemer G . (2002). J. Immunol. Methods, 265, 39–47.
Castedo M, Ferri KF, Blanco J, Roumier T, Larochette N, Barretina J, Amendola A, Nardacci R, Metivier D, Este JA, Piacentini M and Kroemer G . (2001). J. Exp. Med., 194, 1097–1110.
Costantini P, Chernyak BV, Petronilli V and Bernardi P . (1996). J. Biol. Chem., 271, 6746–6751.
Costantini P, Jacotot E, Decaudin D and Kroemer G . (2000). J. Natl. Cancer Inst., 92, 1042–1053.
De Palo G, Mariani L, Camerini T, Marubini E, Formelli F, Pasini B, Decensi A and Veronesi U . (2002). Gynecol. Oncol., 86, 24–27.
Debatin KM, Poncet D and Kroemer G . (2002). Oncogene, 21, 8786–8803.
DeMaria R, Lenti L, Malisan F, d'Agostino F, Tomassini B, Zeuner A, Rippo MR and Testi R . (1997). Science, 277, 1652–1655.
Erdreich-Epstein A, Tran LB, Bowman NN, Wang H, Cabot MC, Durden DL, Vlckova J, Reynolds CP, Stins MF, Groshen S and Millard M . (2002). J. Biol. Chem., 277, 49531–49537.
Feuillard J, Schuhmacher M, Kohanna S, Asso-Bonnet M, Ledeur F, Joubert-Caron R, Bissieres P, Polack A, Bornkamm GW and Raphael M . (2000). Blood, 95, 2068–2075.
Fontana JA and Rishi AK . (2002). Leukemia, 16, 463–472.
Fulda B, Meyer E, Susin SA, Kroemer G and Debatin KM . (2001). Oncogene, 20, 1073–1075.
Goldmacher VS, Bartle LM, Skletskaya S, Dionne CA, Kedersha NL, Vater CA, Han JW, Lutz RJ, Watanabe S, McFarland EDC, Kieff ED, Mocarski ES and Chittenden T . (1999). Proc. Natl. Acad. Sci. USA, 96, 12536–12541.
Gourdier I, Del Rio M, Crabbe L, Candeil L, Copois V, Ychou M, Auffray C, Martineau P, Mechti N, Pommier Y and Pau B . (2002). FEBS Lett., 529, 232.
Green A, Shilkaitis A and Christov K . (1999). Carcinogenesis, 20, 15535–15540.
Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C and Hickman JA . (1999). J. Cell Biol., 144, 903–914.
Hail NJ and Lotan R . (2000). Cancer Epidemiol. Biomarkers Prev., 9, 1293–1301.
Hail NJ and Lotan R . (2001). J. Biol. Chem., 276, 45614–45621.
Hayajneh WA, Colberg-Oley AM, Skaleskaya A, Bartle LM, Lesperance MM, Contopoulos-Ionnidis DG, Kedersha NL and Goldmacher VS . (2001). Virology, 279, 233–240.
Holmes WF, Soprano DR and Soprano KJ . (2002). J. Biol. Chem., 277, 45408–45419.
Hursting SD, Perkins SN, Phang JM and Barrett JC . (2001). J. Nutr., 131, 3092S–3094S.
Hursting SD, Shen JC, Sun XY, Wang TT, Phang JM and Perkins SN . (2002). Mol. Carcinogen., 33, 16–24.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ and Schlesinger PH . (2000). Cell Death Differ., 7, 1166–1173.
Krammer PH . (2000). Nature, 407, 789–795.
Kroemer G, Dallaporta B and Resche-Rigon M . (1998). Annu. Rev. Physiol., 60, 619–642.
Kroemer G and Reed JC . (2000). Nat. Med., 6, 513–519.
Kuwana T, Mackey MR, Perkins GA, Ellisman MH, Latterich M, Schneiter R, Green DR and Newmeyer DD . (2002). Cell, 111, 1–12.
Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S and Korsmeyer S . (2002). Cancer Cell, 2, 183.
Levi MS, Borne RF and Williamson JS . (2001). Curr. Med. Chem., 8, 1349–1362.
Li H, Zhu H, Xu C and Yuan J . (1998). Cell, 94, 491–501.
Lim SJ, Simeone AM, Kim CK and Tari AM . (2002). Int. J. Cancer, 101, 243–247.
Lovat PE, Oliverio S, Ranalli M, Corazzari M, Rodolfo C, Bernassola F, Aughton K, Maccarrone M, Hewson QD, Pearson AD, Melino G, Piacentini M and Redfern CP . (2002). Cancer Res., 62, 5158–5167.
Macho A, Decaudin D, Castedo M, Hirsch T, Susin SA, Zamzami N and Kroemer G . (1996). Cytometry, 25, 333–340.
Marchetti P, Zamzami N, Josph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G and Formstecher P . (1999). Cancer Res., 54, 6257–6275.
Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Rémy R, Xie Z-H, Reed JC and Kroemer G . (1998). J. Exp. Med., 187, 1261–1271.
McCormick AL, Smith VL, Chow D and Mocarski ES . (2003). J. Virol., 77, 631–641.
Metivier D, Dallaporta B, Zamzami N, Larochette N, Susin SA, Marzo I and Kroemer G . (1998). Immunol. Lett., 61, 157–164.
Notario B, Zamora M, Vinas O and Mampel T . (2003). Mol. Pharmacol., 63, 224–231.
Pinton P, Ferrari D, Rapizzi E, Di Virgilio FD, Pozzan T and Rizzuto R . (2001). EMBO J., 20, 2690–2701.
Prinetti A, Basso L, Appierto V, Villani MG, Valsecchi M, Loberto N, Prioni S, Chigorno V, Cavadini E, Formelli F and Sonnino S . (2003). J. Biol. Chem., 278, 5574–5583.
Raffaghello L, Pagnan G, Pastorino F, Cosimo E, Brignole C, Marimpietri D, Montaldo PG, Gambini C, Allen TM, Bogenmann E and Ponzoni M . (2003). Int. J. Cancer, 104, 559–567.
Ranger AM, Malynn BA and Korsmeyer SJ . (2001). Nat. Genet., 28, 113–118.
Rippo MR, Malisan F, Ravagnan L, Condo I, Tomassini B, Costantini P, Todaro M, Susin SA, Rufini A, Kroemer G and Testi R . (2000). FASEB J., 14, 2047–2054.
Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T and Korsmeyer SJ . (2003). Science, 300, 135–139.
Shaker MR, Yang G, Timme TL, Park SH, Kadmon D, Ren C, Ji X, Lee HM, Sehgal I, Anzano M, Sporn MB and Thompson TC . (2000). Clin. Exp. Metastasis, 18, 429–438.
Shimada K, Nakamura M, Ishida E, Kishi M, Yonehara S and Konishi N . (2002). Mol. Carcinog., 35, 127–137.
Singletary SE, Atkinson EN, Hoque A, Sneige N, Sahin AA, Fritsche HAJ, Lotan R, Lu T, Hittelman WN, Bevers TB, Stelling CB and Lippman SM . (2001). Clin. Cancer Res., 8, 2835–2842.
Susin SA, Larochette N, Geuskens M and Kroemer G . (2000). Methods Enzymol., 322, 205–208.
Susin SA, Zamzami N and Kroemer G . (1998). Biochim. Biophys. Acta (Bioenergetics), 1366, 151–165.
Suzuki M, Youle RJ and Tjandra N . (2000). Cell, 103, 645–654.
Thomenius MJ, Wang NS, Reineks EZ, Wang Z and Distelhorst CW . (2003). J. Biol. Chem., 278, 6243–6250.
Wang H, Maurer BJ, Reynolds CP and Cabot MC . (2001). Cancer Res., 61, 5102–5105.
Wang X . (2002). Genes Dev., 15, 2922–2933.
Wei MC, Zong W-X, Cheng EH-Y, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ . (2001). Science, 292, 727–730.
Wu JM, DiPietrantonio AM and Hsieh TC . (2001). Apoptosis, 6, 377–388.
You KR, Wen J, Lee ST and Kim DG . (2002). J. Biol. Chem., 277, 3870–3877.
Zamzami N, Brenner C, Marzo I, Susin SA and Kroemer G . (1998). Oncogene, 16, 2265–2282.
Zamzami N and Kroemer G . (2003). Curr. Biol., 13, R71–R73.
Zorov DB, Filburn CR, Klotz LO, Zweier JL and Sollott SJ . (2000). J. Exp. Med., 192, 1001–1014.
Zou C, Guan Y, Wang J, Wang LE, Liebert M, Grossman HB and Wei Q . (2002). Cancer Lett., 180, 131–137.
Acknowledgements
We thank Dr Victor Goldmacher (ImmunoGen, Cambridge, MA, USA) and Dr Bern Vogelstein (John Hopkins Cancer Center, Baltimore, MA, USA) for cell lines and Nathanael Larochette and Didier Métivier (CNRS, Villejuif, France) for assistance. This work has been supported by a special grant from the Ligue Nationale contre le Cancer, as well as grants from Ligue départmentale contre le Cancer (Seine St Denis), ANRS, FRM, ARC, and European Commission (QLG1-CT-1999-00739 and QLK3-CT-20002-01956) (to GK). PB received a fellowship from the European Commission (MCFI-2000-00943).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Boya, P., Morales, M., Gonzalez-Polo, RA. et al. The chemopreventive agent N-(4-hydroxyphenyl)retinamide induces apoptosis through a mitochondrial pathway regulated by proteins from the Bcl-2 family. Oncogene 22, 6220–6230 (2003). https://doi.org/10.1038/sj.onc.1206827
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206827
Keywords
This article is cited by
-
The expression of galectin-3 in breast cancer and its association with chemoresistance: a systematic review of the literature
Archives of Gynecology and Obstetrics (2019)
-
Reversal of Beta-Amyloid-Induced Neurotoxicity in PC12 Cells by Curcumin, the Important Role of ROS-Mediated Signaling and ERK Pathway
Cellular and Molecular Neurobiology (2017)
-
Arsenic trioxide alleviates airway hyperresponsiveness and promotes apoptosis of CD4+ T lymphocytes: evidence for involvement of the ER stress–CHOP pathway
Irish Journal of Medical Science (2013)
-
N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity
Leukemia (2012)
-
Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response
BMC Cancer (2010)