Research Resource: Diagnostic and Therapeutic Potential of Nuclear Receptor Expression in Lung Cancer
ABSTRACT Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator-activated receptor-γ) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-γ) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment.
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ABSTRACT: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.Biochemical and Biophysical Research Communications 01/2014; · 2.28 Impact Factor
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ABSTRACT: The consumption of high-calorie foods combined with less physical exercise has increased the prevalence of obesity. Obesity is also associated with high blood pressure, atherosclerosis, insulin resistance, diabetes, impaired host defense, and the risk of some cancers. Because PPARγ is a central player that participates in various biological responses, including lipid metabolism, inflammation, and cell proliferation, further understanding of the lipid metabolic sensor PPARγ is necessary to reduce the incidence of metabolic diseases and cancer.Archives of Pharmacal Research 01/2015; 38(3). DOI:10.1007/s12272-015-0559-x · 1.75 Impact Factor
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ABSTRACT: Prostate cancer (PCa) is the major cause of cancer-related death among the male population of Western society, and androgen-deprivation therapy (ADT) represents the first line in PCa treatment. However, although androgen receptor (AR) expression is maintained throughout the various stages of PCa, ADT frequently fails. Clinical studies have demonstrated that different androgen/AR signaling pathways operate in target tissues. AR stimulates growth and transformation of target cells, but under certain conditions slows down their proliferation. In this review, we discuss the role of AR in controlling different functions of mesenchymal and transformed mesenchymal cells. Findings here presented support the role of AR in suppressing proliferation and stimulating migration of stromal cells, with implications for current approaches to cancer therapy.Frontiers in Endocrinology 01/2014; 5:225. DOI:10.3389/fendo.2014.00225