Activity of retinoic acid receptor‐γ selectively binding retinoids alone and in combination with interferon‐γ in breast cancer cell lines

Widschwendter, Martin; Daxenbichler, Günter; Čulig, Zoran; Michel, Serge; Zeimet, Alain G.; Mörtl, M; Widschwendter, Andreas; Marth, Christian

doi:10.1002/(sici)1097-0215(19970502)71:3<497::aid-ijc31>3.3.co;2-4

Cited by 15 publications

(26 citation statements)

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“…AHPN and its analogs are a class of retinoid-related compounds that effectively induce apoptosis of many cancer types (Schadendorf et al, 1995;Shao et al, 1995;Li et al, 1996Li et al, , 1998Li et al, , 2000Oridate et al, 1997;Widschwendter et al, 1997;Hsu et al, 1997a, b;Adachi et al, 1998;Dawson et al, 1998;Langdon et al, 1998;Gianni and de The, 1999;Liang et al, 1999;Sun et al, 1999;Holmes et al, 2002). They are known to activate JNK (Zhang et al, , 2003Wan et al, 2001;Garattini et al, 2004;Boisvieux-Ulrich et al, 2005), which is required for maximal apoptosis induction and precedes mitochondrial depolarization.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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Section: Introductionmentioning

confidence: 99%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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“…Interestingly, IFNg and RA are well known for their ability to evoke a synergistic effect, which generally leads to an enhanced induction of target gene(s) and an exacerbation of the associated biological response(s). The impact of this synergism has been observed in a wide range of malignant tumour cell types, including breast, oral, neuroblastoma, leukemic and renal cancer cells (Ho, 1985;Windbichler et al, 1996;Widschwendter et al, 1997;Guzhova et al, 2001;Yang et al, 2001;Hu et al, 2002), but has remained largely unexplored in pancreatic tumour cells and, therefore, raises important questions.…”

Section: Introductionmentioning

confidence: 99%

Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways

et al. 2005

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The transmembrane mucin, MUC4, is aberrantly expressed with a high incidence in human pancreatic adenocarcinomas and plays an important role in the pathogenesis of the disease. Our recent studies have shown that interferon-c (IFNc) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNc occurs via a novel pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1), whereas its stimulation by RA requires mediation by the transforming growth factor b-2 (TGFb-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNc and RA in MUC4 regulation in pancreatic tumour cells. We demonstrate that these reagents exert a synergistic induction of MUC4. Interestingly, while the upregulation of STAT-1 by IFNc is partially inhibited by RA, IFNc is shown to repress RA-driven TGFb-2 induction, pointing to the involvement of alternative mechanism(s) in IFNc-RA synergism. Moreover, a dose-dependent and cooperative induction of MUC4 promoter activity suggests a regulation at the transcriptional level, most likely by STAT-1 and RAR/RXR (RA receptor/retinoic X receptor) or other IFNc/RAinduced secondary intermediate effectors. Our findings provide potential mechanisms that may account for the aberrant expression of MUC4 in pancreatic tumour cells and expose a novel molecular mechanism of gene induction, whereby a reprogramming of signalling pathway through alternative route(s) operates during a synergistic interaction of biological modifiers.

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“…The RA-provoked growth effects were synergistically amplified by a combination with interferon γ (IFN-γ), and this was accompanied by upregulation of the mRNA for nuclear receptor RAR-γ (retinoic acid receptor-γ) (Widschwendter et al, 1995(Widschwendter et al, , 1996. Similar effects were also achieved with the RAR-γ selective agonists CD2325 and CD437 (Widschwendter et al, 1997). In animals, administration of retinoids inhibits the initiation and promotion of mammary tumours induced by carcinogens (Moon and Mehta, 1990;Costa, 1993).…”

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confidence: 57%

“…Recently, we and others (Widschwendter et al, 1995;Fanjul et al, 1996) demonstrated RAR-γ to be involved in retinoid-mediated antiproliferative effects. Synthetic retinoid analogues CD437 and CD2325, which demonstrated RAR-γ selectivity and a strong antiproliferative potency in breast cancer cells (Shao et al, 1995;Widschwendter et al, 1997), showed the same effect on PRL-R expression as did natural substances.…”

Section: Discussionmentioning

confidence: 95%

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Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro

Widschwendter

Welte

et al. 1998

Br J Cancer

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Summary Two recent papers demonstrate that prolactin plays an important role in the induction and progression of mammary tumours. Retinoids have been shown to be potent inhibitors of breast carcinogenesis. We studied expression of prolactin receptor mRNA in human breast cancer cell lines MCF-7, SKBR-3, T47D and BT-20 treated with and without retinoids using Northern blot and a quantitative polymerase chain reaction (PCR) method. In all cell lines, all-trans-and 9-cis-retinoic acid, as well as the retinoic acid receptor γ (RAR-γ) selective agonists CD2325 and CD437 (1 µM), were able to down-regulate prolactin receptor. After 1 h, a significant reduction was detectable and maximal effect was achieved after 24 h of treatment. Pretreatment with retinoic acid also reduced the prolactin-/prolactin receptordependent signal transduction and activation of transcription 5 (STAT-5) activation in T47D cells. Cycloheximide failed to abrogate the retinoic acid-induced decline in prolactin receptor mRNA levels, indicating that this effect was not dependent upon continuing protein synthesis. Similarly, no change in the stability of prolactin receptor mRNA was observed during 12 h of retinoic acid treatment. In conclusion, our results demonstrate that retinoids are able to inhibit the expression of prolactin receptor message, which encodes an important growth factor receptor in breast cancer cells. This action could be responsible for the anti-tumour effects of retinoids.

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Activity of retinoic acid receptor‐γ selectively binding retinoids alone and in combination with interferon‐γ in breast cancer cell lines

Cited by 15 publications

References 0 publications

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Synergistic induction of the MUC4 mucin gene by interferon-γ and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways

Retinoic acid modulates prolactin receptor expression and prolactin-induced STAT-5 activation in breast cancer cells in vitro

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