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.
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.


CONCLUSIONS
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.
Andela
Valentine B
VB
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
Rosier
Randy N
RN
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D008024:Ligands; D046911:Macromolecular Substances / Q000037:antagonists & inhibitors; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology; D009363:Neoplasm Proteins; D021381:Protein Transport / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D012176:Retinoids; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D007976:Leupeptins; D008024:Ligands; D046911:Macromolecular Substances; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D012176:Retinoids; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde