PGC1α/CEBPB/CPT1A axis promotes radiation resistance of nasopharyngeal carcinoma through activating fatty acid oxidation

Abstract

The PPAR coactivator‐1α (PGC1α) is an important transcriptional co‐activator in control of fatty acid metabolism. Mitochondrial fatty acid oxidation (FAO) is the primary pathway for the degradation of fatty acids and promotes NADPH and ATP production. Our previous study demonstrated that upregulation of carnitine palmitoyl transferase 1 A (CPT1A), the key regulator of FAO, promotes radiation resistance of nasopharyngeal carcinoma (NPC). In this study, we found that high expression of PGC1α is associated with poor overall survival in NPC patients after radiation treatment. Targeting PGC1α could sensitize NPC cells to radiotherapy. Mechanically, PGC1α binds to CCAAT/enhancer binding protein β (CEBPB), a member of the transcription factor family of CEBP, to promote CPT1A transcription, resulting in activation of FAO. Our results revealed that the PGC1α/CEBPB/CPT1A/FAO signaling axis promotes radiation resistance of NPC. These findings indicate that the expression of PGC1α could be a prognostic indicator of NPC, and targeting FAO in NPC with high expression of PGC1α might improve the therapeutic efficacy of radiotherapy.

Fat-lowering effects of isorhamnetin are via NHR-49-dependent pathway in Caenorhabditis elegans

“…The PPAR may have different target genes dependent to co-factors, such as C/EBPs and PPAR coactivator 1α (PGC1α) ( Chung et al., 2016 ); PGC1α and C/EBPβ were both involved in the increased fatty acid oxidation by CPT1 in human nasopharyngeal cancer cells ( Du et al., 2019 ). Homologs of these co-factors are MDT-15/PGC1α and CEBP-2/C/EBP in C. elegans , respectively ( Lin et al., 2019 , Xu et al., 2015 ).…”

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…168 Recent studies also show that knocking down PPAR coactivator 1α (PGC1α), an important transcriptional coactivator regulating CPT1A and CPT1B, obviously decreases the ratio of NADPH/NADP + and ATP levels, impairing radiation resistance in nasopharyngeal carcinoma (NPC) cells. 169 What's more, AMPactivated protein kinase (AMPK) also regulates the function of FAO in maintaining NADPH homeostasis and promotes tumor cell survival under oxidative stress or metabolic stress. [170][171][172][173] THERAPEUTIC IMPLICATIONS FOR TARGETING NADPH METABOLISM Compared with their normal counterparts, many types of cancer cell have increased oxidative stress and the upregulation of antioxidant capacity.…”

Baicalin Represses C/EBPβ via Its Antioxidative Effect in Parkinson’s Disease

“…Usually, it is mitochondria's ability to produce ATP appropriately in response to energy demands [16]. Meanwhile, the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ), which is expressed in the brain, is also involved in the regulation of ATP synthesis [17]. Remarkably, C/EBPβ−/− mice exhibit resistance to excitotoxicityinduced neuronal cell death, which indicates that C/EBPβ might regulate gene expression implicated in brain damage [18].…”