Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small-cell lung cancer cells
| Autor: | Yong Lin, Shuguang Leng, Kieu Do, Steven A. Belinsky, Wenshu Chen, Mathewos Tessema, Piotr T. Filipczak, Bryanna Saxton |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Cell Survival Diazooxonorleucine Down-Regulation Biology Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Humans Cytotoxicity Molecular Biology Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Cell Proliferation Cisplatin Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) Cell growth Endoplasmic reticulum Drug Synergism Hexosamines Gene Expression Regulation Neoplastic 030104 developmental biology Apoptosis A549 Cells 030220 oncology & carcinogenesis biology.protein Unfolded protein response Cancer research Binding immunoglobulin protein medicine.drug |
| Zdroj: | Mol Carcinog |
| ISSN: | 1098-2744 |
| Popis: | Platinum anticancer agents are essential components in chemotherapeutic regimens for non-small cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum-based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino-sugar N-acetyl-glucosamine (GlcNAc) for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by combination of cisplatin with HBP inhibition. Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFAT impaired cell proliferation and exerted a synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose-regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response. Suppressing GFAT activity resulted in downregulation of BiP that activated inositol-requiring enzyme 1α (IRE1α), a sensor protein of unfolded protein response, and exacerbated cisplatin-induced cell apoptosis. These data identify GFAT-mediated HBP as a target for improving platinum-based chemotherapy for NSCLC. |
| Databáze: | OpenAIRE |
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