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The proteosome inhibitor MG132 attenuates retinoic acid receptor trans-activation and enhances trans-repression of nuclear factor kappaB. Potential relevance to chemo-preventive interventions with retinoids.

Andela VB, Rosier RN - Mol. Cancer (2004)

Bottom Line: Nuclear factor kappa B (NFkappaB) is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression.At-RA [0.1-1 microM] dose-dependently activated RAR and coordinately trans-repressed NFkappaB, while AGN193109 [1-10 microM] dose-dependently antagonized the effects of at-RA.We conclude that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedics & The James P, Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue Box 665, Rochester, New York, 14642, USA. Valentine_Andela@urmc.rochester.edu

ABSTRACT

Background: Nuclear factor kappa B (NFkappaB) is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFkappaB blockade results in the reciprocal induction of retinoic acid receptors (RARs). Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFkappaB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA) and the pan-RAR antagonist, AGN193109.

Results: At-RA [0.1-1 microM] dose-dependently activated RAR and coordinately trans-repressed NFkappaB, while AGN193109 [1-10 microM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9) and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1), in a manner consistent with the putative roles of NFkappaB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 microM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFkappaB.

Conclusion: We conclude that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

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A reductionist model for optimizing the anticancer property of retinoids. The classical IκB-NFκB signaling cascade proceeds through the sequential phosphorylation, ubiquitination (ub) and proteosomal degradation of IκBα and the coordinate release and nuclear translocation of NFκB. Hyper-activation of NFκB in cancer can be overridden by hyper-activating RAR with retinoids. As such retinoid therapy induces malignant reversion but is associated with retinoid toxicity. Proteosome inhibitors quell RAR trans-activation and enhance RAR trans-repression of NFκB.
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Figure 6: A reductionist model for optimizing the anticancer property of retinoids. The classical IκB-NFκB signaling cascade proceeds through the sequential phosphorylation, ubiquitination (ub) and proteosomal degradation of IκBα and the coordinate release and nuclear translocation of NFκB. Hyper-activation of NFκB in cancer can be overridden by hyper-activating RAR with retinoids. As such retinoid therapy induces malignant reversion but is associated with retinoid toxicity. Proteosome inhibitors quell RAR trans-activation and enhance RAR trans-repression of NFκB.

Mentions: At the system level understanding of cancer biology, "overly" simplistic models are confounded by redundancies, feed-back loops and multiple signal integration, characteristic of robust regulatory systems. With better understanding of molecular circuits and signaling schemes, we are better skilled at manipulating biological systems to desired ends. Case in point, we demonstrate that the proteosome inhibitor MG132 blocks RAR degradation and quells RAR trans-activity while enhancing RAR trans-repression of NFκB (Fig 6). This repression is independent of the effect of proteosome inhibitors on the IκB-NFκB signaling cascade, given the compounded suppression NFκB responsiveness in mIκB-Line 1 cells expressing a dominant negative IκBα, not susceptible to proteosomal degradation. These results resound the promise of proteosome inhibitors in the anticancer arsenal [38-40]. We propose the combinatorial use of proteosome inhibitors and retinoids, as a strategy for enhancing chemo-preventive activity and possibly limiting retinoid toxicity.


The proteosome inhibitor MG132 attenuates retinoic acid receptor trans-activation and enhances trans-repression of nuclear factor kappaB. Potential relevance to chemo-preventive interventions with retinoids.

Andela VB, Rosier RN - Mol. Cancer (2004)

A reductionist model for optimizing the anticancer property of retinoids. The classical IκB-NFκB signaling cascade proceeds through the sequential phosphorylation, ubiquitination (ub) and proteosomal degradation of IκBα and the coordinate release and nuclear translocation of NFκB. Hyper-activation of NFκB in cancer can be overridden by hyper-activating RAR with retinoids. As such retinoid therapy induces malignant reversion but is associated with retinoid toxicity. Proteosome inhibitors quell RAR trans-activation and enhance RAR trans-repression of NFκB.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC398417&req=5

Figure 6: A reductionist model for optimizing the anticancer property of retinoids. The classical IκB-NFκB signaling cascade proceeds through the sequential phosphorylation, ubiquitination (ub) and proteosomal degradation of IκBα and the coordinate release and nuclear translocation of NFκB. Hyper-activation of NFκB in cancer can be overridden by hyper-activating RAR with retinoids. As such retinoid therapy induces malignant reversion but is associated with retinoid toxicity. Proteosome inhibitors quell RAR trans-activation and enhance RAR trans-repression of NFκB.
Mentions: At the system level understanding of cancer biology, "overly" simplistic models are confounded by redundancies, feed-back loops and multiple signal integration, characteristic of robust regulatory systems. With better understanding of molecular circuits and signaling schemes, we are better skilled at manipulating biological systems to desired ends. Case in point, we demonstrate that the proteosome inhibitor MG132 blocks RAR degradation and quells RAR trans-activity while enhancing RAR trans-repression of NFκB (Fig 6). This repression is independent of the effect of proteosome inhibitors on the IκB-NFκB signaling cascade, given the compounded suppression NFκB responsiveness in mIκB-Line 1 cells expressing a dominant negative IκBα, not susceptible to proteosomal degradation. These results resound the promise of proteosome inhibitors in the anticancer arsenal [38-40]. We propose the combinatorial use of proteosome inhibitors and retinoids, as a strategy for enhancing chemo-preventive activity and possibly limiting retinoid toxicity.

Bottom Line: Nuclear factor kappa B (NFkappaB) is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression.At-RA [0.1-1 microM] dose-dependently activated RAR and coordinately trans-repressed NFkappaB, while AGN193109 [1-10 microM] dose-dependently antagonized the effects of at-RA.We conclude that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Orthopaedics & The James P, Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue Box 665, Rochester, New York, 14642, USA. Valentine_Andela@urmc.rochester.edu

ABSTRACT

Background: Nuclear factor kappa B (NFkappaB) is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFkappaB blockade results in the reciprocal induction of retinoic acid receptors (RARs). Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFkappaB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA) and the pan-RAR antagonist, AGN193109.

Results: At-RA [0.1-1 microM] dose-dependently activated RAR and coordinately trans-repressed NFkappaB, while AGN193109 [1-10 microM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9) and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1), in a manner consistent with the putative roles of NFkappaB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 microM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFkappaB.

Conclusion: We conclude that reciprocal interactions between NFkappaB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

Show MeSH
Related in: MedlinePlus