Abstract
BackgroundRetinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers.ResultsUsing different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10) and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2) genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS) is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s) of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells.ConclusionsThis study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to cancer therapy-mediated apoptosis in breast cancer cells, independently of cIAP2. Our data support the use of NF-kappaB pathway activation as a marker for screening that will help to develop novel retinoids, or retinoid-based combination therapies with improved efficacy.
Highlights
Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention
By comparing different breast cancer cell lines, we found that pretreatment with retinoic acid can antagonize chemotherapy-induced cell death in a cell- dependent manner, which correlates with the activation of NF-B/cIAP2 signaling pathway (s)
ZR-75-1 cells responded to 9-cis-RA in a similar manner to T47D cells showing a reduction in sensitivity to etoposide upon pretreatment with 9-cis-RA. These results show that the protection against etoposide-mediated cell death exerted by 9-cis-RA is not restricted to T47D breast cancer cells. cIAP2 is not critically involved in the protection of etoposide-induced apoptosis by 9-cis-RA Previous reports have shown that exogenous overexpression of cIAP2 can abrogate apoptosis induced by genotoxic anticancer drugs such as etoposide, but not death receptor-mediated apoptosis in a NF-B null background [41]
Summary
Through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers. The search for alternatives to, and adjuvants for chemotherapy of breast cancer to prolong survival after the development of chemoresistance or during chemotherapy constitutes an area of intensive research In this respect the concept of “cancer differentiation therapy” has emerged as an approach that intends to force a tumor cell to acquire a less aggressive differentiated phenotype, concomitant with growth inhibition and to induce cell death upon terminal differentiation. Previous studies suggest that retinoids inhibit cell growth interfering with growth factor signaling pathways [17,18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
