Peroxisome proliferator-activated receptor γ improves pemetrexed therapeutic efficacy in non-squamous non-small cell lung cancer
AJTR Copyright © 2021..
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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
American journal of translational research - 13(2021), 4 vom: 01., Seite 2296-2307 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hang, Tianxing [VerfasserIn] |
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| Themen: |
Hypoxanthine-guanine phosphoribosyl transferase |
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| Anmerkungen: |
Date Revised 23.05.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM325667721 |
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| 245 | 1 | 0 | |a Peroxisome proliferator-activated receptor γ improves pemetrexed therapeutic efficacy in non-squamous non-small cell lung cancer |
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| 500 | |a Date Revised 23.05.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a AJTR Copyright © 2021. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a NF-κB | |
| 650 | 4 | |a Peroxisome proliferator-activated receptor γ | |
| 650 | 4 | |a hypoxanthine-guanine phosphoribosyl transferase | |
| 650 | 4 | |a non-squamous non-small cell lung cancer | |
| 650 | 4 | |a pemetrexed | |
| 700 | 1 | |a Yang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiujuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Ning |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Jingwen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Youzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xiaomin |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shengqing |e verfasserin |4 aut | |
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