Peroxisome proliferator-activated receptor γ improves pemetrexed therapeutic efficacy in non-squamous non-small cell lung cancer.

Abstract

OBJECTIVE:

The folic acid analog pemetrexed (PMX) is recommended for the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, the mechanisms underlying PMX cytotoxicity in NSCLC remain to be fully explored.

METHODS:

PMX effect was evaluated in a urethane-induced lung adenocarcinoma mouse model. The interaction between PMX and intracellular proteins, particularly peroxisome proliferator-activated receptor γ (PPARγ), was investigated. The role of PPARγ in mediating pemetrexed cytotoxicity was investigated using NSCLC cell lines, mouse models and clinical specimens.

RESULTS:

This study found that PPARγ expression was correlated with prolonged progression-free survival in NSCLC patients. PPARγ downregulated hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a key enzyme for nucleotide salvage synthesis, thereby sensitizing cells to PMX inhibition on nucleotide de novo synthesis. PMX was also a candidate partial agonist of PPARγ, and PMX-activated PPARγ bound to NF-κB and transcriptionally suppressed the NF-κB target gene, c-Myc. PMX inhibited tumor growth by activating PPARγ in a urethane-induced lung cancer model characterized by elevated NF-κB activity.

CONCLUSION:

PPARγ improves pemetrexed therapeutic efficacy in non-squamous NSCLC. The cytotoxicity effect of PMX can be synergized by activating PPARγ and thereby inhibiting NF-κB pathway.

• Authors: Tianxing Hang, Li Yang, Xiujuan Zhang, Jing Li, Feng Long, Ning Zhu, Ying Li, Jingwen Xia, Youzhi Zhang, Peng Zhang, Yuanyuan Zhang, Xiaomin Wei, Shengqing Li
• Journal: American journal of translational research (Am J Transl Res) Vol. 13 Issue 4 Pg. 2296-2307 ( 2021) ISSN: 1943-8141 [Print] United States
• PMID: 34017390 (Publication Type: Journal Article)
• Copyright: AJTR Copyright © 2021.