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.

Inhibition of Cancer Cell Proliferation by PPARγ Is Mediated by a Metabolic Switch that Increases Reactive Oxygen Species Levels

“…To test this hypothesis, we analyzed the effects of pioglitazone treatment on cell cycle progression and the levels of reactive oxygen species in the lung cancer cell lines. Using DNA content analysis by FACS we found that pioglitazone treatment caused G1 arrest in both NCI-H2347 and NCI-H1993 cells (Figures 3A and 3B) but not in NCI-H1299 and NCI-H1395 cells (Figures S1A and S1B) that are essentially PPARγ-negative (Jeong et al, 2012). The pioglitazone-induced cell cycle arrest coincided with a marked reduction in the levels of phosphorylated RB in the NCI-H2347 and NCI-H1993 cells within 24 hours of treatment (Figure 3C), but not in the PPARγ-negative NCI-H1299 and NCI-H1395 cells (Figure S1C).…”

“…For the cistrome analysis, we used chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) with NCI-H2347 and NCI-H1993 lung adenocarcinoma cells, which express PPARγ at high levels and whose growth is inhibited by TZDs such as pioglitazone and troglitazone (Jeong et al, 2012). We found 2225 regions in NCI-H2347 cells and 1419 in NCI-H1993 cells with a significantly increased occupancy for PPARγ (Figure 1A, Table S1).…”

“…Likewise, NAC prevented RB hypophosphorylation by pioglitazone in HCC-1954 and HCC-1187 breast cancer cells (Figure S1I). Second, we tested if increased ROS levels were required for the growth inhibition observed for TZDs in vivo (Jeong et al, 2012). For this purpose we tested the effects of NAC on pioglitazone-mediated inhibition of NCI-H2347 tumor xenograft growth.…”

“…In principle, the activation or inhibition of transcriptional master regulators of metabolic processes presents another promising strategy to target cancer metabolism and may achieve a more selective response. In this vein, our group recently found that PPARγ is expressed at high levels in a subset of non-small cell lung cancer cells (Jeong et al, 2012), where its activation with thiazolidinediones (TZDs) causes growth inhibition both in vitro and in vivo . Also, growth-suppressing effects of PPARγ and TZDs have been shown for a variety of other cancers (reviewed in (Koeffler, 2003; Peters et al, 2012)).…”

The multifaceted factor peroxisome proliferator-activated receptor γ (PPARγ) in metabolism, immunity, and cancer

“…Many investigations are now aimed at determining whether PPARc and its ligands could be used as therapeutics for cancer treatment. Jeong et al showed that PPARc-positive lung cancer cell lines are more sensitive to the anti-cancerous effects of its ligands, implicating its possible usage for cancer therapy (Jeong et al 2012). In a phase 2 clinical trial, troglitazone showed that it could inhibit the growth of prostate cancer cells .…”