Inhibitory effect of PPARγ on NR0B1 in tumorigenesis of lung adenocarcinoma

Abstract

NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor γ (PPARγ) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARγ was examined. The transactivation ability of PPARγ was inhibited by NR0B1 in lung adenocarcinoma, and the N-terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co-immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARγ. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARγ overexpression. ALDH activity increased by treatment with PPARγ inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARγ expression was a negative prognostic factor in Pathological-Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARγ on the malignant grade of lung adenocarcinoma.

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…Last but not least, robust data from myeloid-specific bitransgenic mouse model allow us to hypothesize that anti-inflammatory PPAR γ in myeloid-lineage cells plays a key role in controlling proinflammatory cytokine synthesis, myeloid-derived suppressor cell expansion, immunosuppression, and the development of cancer [74]. Finally, recent evidence suggests that PPAR γ is able to induce apoptosis in lung cancer, although it can be inhibited by NR0B1, an orphan nuclear receptor whose knockdown reduces tumorigenic and antiapoptotic potential [75]. …”

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma

“…PPARG has recently attracted interest as the potential therapeutic target for a variety of malignancies [3]. A number of animal models [4], cell lines [5,6], and clinical trials [NCT00923949, NCT01199068, NCT01199055] demonstrated that activation of PPARgamma impedes lung tumor progression and suggest that PPARG ligands may serve as potential therapeutic agents for nonsmall cell lung cancer (NSCLC), with the emphasis on lung adenocarcinoma [7,8]. For instance, Ni et al's study showed that the activation of PPARG could inhibit the prolif-eration of EGFR-TKI-resistant lung adenocarcinoma cells and lead to a better survival rate [8].…”

PPARG Drives Molecular Networks as an Inhibitor for the Pathologic Development and Progression of Lung Adenocarcinoma

“…Locating on chromosome 3 (base pairs 12,287,485 to 12,434,356), PPARG encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors-Peroxisome proliferator-activated receptor γ (PPARγ), which have been shown to possesses an antagonistic function against LA (PMID: 22843091). However, so far, limited knowledge of this PPARG-inhibiting-LA mechanism is known [3]. On the one hand, it has been shown that the expression of PPARG was reduced in LA progression cells [4], and the low PPARG expression was strictly correlated with poor prognosis of stage IA LA [3].…”

“…However, so far, limited knowledge of this PPARG-inhibiting-LA mechanism is known [3]. On the one hand, it has been shown that the expression of PPARG was reduced in LA progression cells [4], and the low PPARG expression was strictly correlated with poor prognosis of stage IA LA [3]. On the other hand, increased expression of PPARG has been positively associated with a better survival rate of LA patients [4].…”

“…Ni et al's work showed that overexpression of PPARγ could inhibit the drug resistance effect of gefitinib in the treatment of LA by reducing the proliferation of gefitinib-resistant cells [4]. Susaki et al showed that PPARG could inhibit the tumorigenic potential of NR0B1 in LA [3]. However, more studies are needed to identify the underlying mechanism of the role that PPARG plays in the pathological development of LA.…”