Background Head and neck squamous cell carcinoma (HNSCC) requires new treatments and targeted approaches to improve survival. The peroxisome proliferator‐activated receptor γ (PPARγ) and retinoic X receptor alpha (RXRα) nuclear receptor pathways may be targetable with repurposed Food and Drug Administration (FDA)‐approved agents for prevention and treatment. Methods Oral cancer and leukoplakia cell lines were treated with the PPARγ agonist (pioglitazone) and RXRα activator (bexarotene). PPARγ activation, cellular proliferation, apoptosis activity and phenotype, including the pharmacodynamic marker, involucrin (IVL), were subsequently analyzed using a reporter gene assay, genomic data, MTT assay and western blot. Results Microarray analysis of HNSCC tumor versus normal tissue shows IVL expression is significantly increased in normal tissue compared to HNSCC tumors (p < 0.0001). In MSK Leuk1 and CA 9‐22 cell lines, pioglitazone increases PPARγ DNA binding activity and IVL promoter activity in a dose dependent manner (p < 0.01 and p < 0.0001). Combination treatment with pioglitazone and bexarotene increases PPARγ DNA binding activity and IVL promoter activity (p < 0.01 and p < 0.0001). MTT analysis shows decreases in cell proliferation when cells are treated with pioglitazone and bexarotene. Decreases in cell proliferation are significant to at least p < 0.05 for all combination versus single agent treatments. Western blot on whole‐cell lysate from cells treated with pioglitazone and bexarotene alone or in combination for IVL showed increased protein levels with combination treatment. Conclusions Targeting the PPARγ/RXRα heterodimer with pioglitazone and bexarotene was effective in this preclinical project. This was functional in both preneoplastic and oral cancer cell lines. A better understanding of the molecular mechanism on downstream effects on cellular proliferation could potentially have implications clinically, both in oral preneoplasia and possibly head and neck cancer; however, more research needs to be done to explore the potential these medications have in chemoprevention.
Effective prevention and monitoring of head and neck malignancy is a critical component of disease control which is significantly underdeveloped. Currently, no validated biomarkers or therapies for human aerodigestive preneoplasia exist. We have increasing interest in PPARγ mediated therapy for oral leukoplakia reversal based on our preliminary clinical trial results. Involucrin expression is associated with squamous differentiation and we hypothesize involucrin would be involved with PPARγ upregulation in differentiation therapies. In our present study we examined the use of involucrin as marker of PPARγ activity in response to treatment and effect of bexarotene on pioglitazone mediated PPARγ activation in oral leukoplakia. In an analysis of an Affymetrix database of human head and neck tumors (41 tumors compared to 13 normal oral mucosa samples), we found involucrin is expressed 5.6fold higher in normal versus tumor samples (P<0.0001). We found pioglitazone upregulates PPARγ DNA binding activity and involucrin promoter activity via reporter gene assay. Bexarotene positively effects pioglitazone upregulation of these genes via reporter gene assay and increases protein expression via western blot analysis We conclude the PPARγ activator, pioglitazone, can activate involucrin, which may be useful in upregulating differentiation in oral preneoplasia in clinical trialsin combination with bexarotene. Also involucrin has potential use as a biomarker of disease response to treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1861. doi:10.1158/1538-7445.AM2011-1861
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