Clinical relevance of increased retinoid and cAMP transcriptional programs in tumor cells rendered non-malignant by dominant negative inhibition of NFkappaB.
We previously reported reciprocal regulation of extracellular matrix degrading enzymes and their endogenous inhibitors by NFkappaB. As such, dominant negative inhibition of NFkappaB in a murine lung alveolar carcinoma cell, Line 1, afforded a decrease in malignant proclivity [Cancer Res. 60(23) (2000) 6557-6562]. Contrasting the gene expression profile of malignant Line 1 tumor cells (WT-Line 1) and their non-malignant counterparts transduced with a dominant negative inhibitor of NFkappaB (mIkappaB-Line 1), we observed upregulated retinoic acid receptors (RARs) and the cAMP response element modulator (CREM), in mIkappaB-Line 1 tumor cells, and utilized heterologous promoter-reporter constructs to confirm enhanced responsiveness. We translate these findings by inducing retinoid and cAMP transcriptional programs in WT-Line 1 tumor cells with pharmacologic doses of all-trans retinoic acid (at-RA) and pentoxyfilline (PTX), respectively, and demonstrate suppression of NFkappaB activity, tumor cell derived matrix metalloprotease 9 activity, tumor cell invasiveness in vitro and spontaneous metastasis in vivo. Our results are consistent with the putative role of retinoids and cAMP in the malignant reversion of tumor cells and illustrative of the binary nature of transcriptional programs that modulate malignant progression.
Andela
Valentine B
VB
Center for Musculoskeletal Research, University of Rochester Medical Center, 575 Elmwood Avenue, #1-7534, Rochester, NY 14642, USA. valentine_andela@umrc.rochester.edu
Gingold
Brett I
BI
Souza
Mary D
MD
O'Keefe
Regis J
RJ
Puzas
Edward J
EJ
Schwarz
Edward M
EM
Rosier
Randy N
RN
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D018450:Disease Progression; D004338:Drug Combinations; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010431:Pentoxifylline / Q000494:pharmacology*; D011509:Proteoglycans / Q000494:pharmacology; D012176:Retinoids / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004338:Drug Combinations; D016166:Free Radical Scavengers; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D012176:Retinoids; C059485:matrigel; D014212:Tretinoin; D003094:Collagen; D000242:Cyclic AMP; D010431:Pentoxifylline