An indispensable role of CPT-1a to survive cancer cells during energy stress through rewiring cancer metabolism

Luo, Jingtao; Hong, Yun; Tao, Xiaoan; Wei, Xi; Zhang, Lun; Li, Qiang

doi:10.1007/s13277-016-5382-6

Cited by 20 publications

(13 citation statements)

References 26 publications

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“…Hexameric CPT1A might form hetero-oligomeric complexes with other enzymes and mitochondrial channel proteins, such as long-chain acyl-CoA synthetase (ACSL) and voltage-dependent anion channel (VDAC), to facilitate the transfer of fatty acids into mitochondria [56]. Consistent with our results, CPT1A expression is increased in tumor specimens of pancreatic ductal adenocarcinoma and ovarian cancer and is associated with chemotherapy resistance or poor survival, whereas CPT1A knockdown induces energy stress, cell-cycle arrest, and sensitivity to glucose deprivation in cancer cells or inhibits xenograft growth [57,58]. Alternative splicing of the same gene might produce two CPT1A isoforms, termed CPT1Av1 and CPT1Av2, which show differences in 17 amino acids at the C-terminal region.…”

Section: Discussionsupporting

confidence: 87%

Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection

Abudula¹,

Rouzi²,

Xu³

et al. 2019

Bosn J of Basic Med Sci

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Aberrant metabolic regulation has been observed in human cancers, but the corresponding regulation in human papillomavirus (HPV) infection-associated cervical cancer is not well understood. Here, we explored potential biomarkers for the early prediction of cervical carcinoma based on the metabolic profile of uterine cervical tissue specimens that were positive for HPV16 infection. Fifty-two fresh cervical tissues were collected from women confirmed to have cervical squamous cell carcinoma (SCC; n = 21) or cervical intraepithelial neoplasia (CIN) stages II-III (n = 20). Eleven healthy women constituted the controls (negative controls [NCs]). Real-time polymerase chain reaction (PCR) was performed to detect HPV infection in the tissues. High-resolution magic angle spinning nuclear magnetic resonance was utilized for the analysis of the metabolic profile in the tissues. The expression of rate-limiting enzymes involved in key metabolic pathways was detected by reverse-transcription quantitative PCR. An independent immunohistochemical analysis was performed using 123 cases of paraffin-embedded cervical specimens. A profile of 17 small molecular metabolites that showed differential expression in HPV16-positive cervical SCC or CIN II-III compared with HPV-negative NC group was identified. According to the profile, the levels of α-and β-glucose decreased, those of lactate and low-density lipoproteins increased, and the expression of multiple amino acids was altered. Significantly increased transcript and protein levels of glycogen synthase kinase 3 beta (GSK3β) and glutamate decarboxylase 1 (GAD1) and decreased transcript and protein levels of pyruvate kinase muscle isozyme 2 (PKM2) and carnitine palmitoyltransferase 1A (CPT1A) were observed in the patient group (p < 0.05). HPV infection and cervical carcinogenesis drive metabolic modifications that might be associated with the aberrant regulation of enzymes related to metabolic pathways.

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Section: Discussionsupporting

confidence: 87%

Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection

Abudula¹,

Rouzi²,

Xu³

et al. 2019

Bosn J of Basic Med Sci

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“…Additionally, ROS-dependent regulation of energy metabolism can drive the carbohydrate flux to pentose phosphate pathway, thereby increasing the NADPH level to counteract intracellular ROS [45]. Furthermore, fatty acid oxidation key enzyme carnitine palmitoyltransferase 1A (CPT-1A) maintains intracellular redox and energy homeostasis via generation of NADPH and GSH during energy stress [46]. Cancer cells can rewire metabolic pathways in response to changes in cellular energy and nutrient status, suggesting the complexity of targeting cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: ROS/KRAS/AMPK signaling determines gemcitabine-induced pancreatic cancer stem-like cell property in vitro

Zhao¹,

Li²,

Duan³

et al. 2018

Oncotarget

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Poor prognosis of pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM), the standard chemotherapy. Dysregulated glucose metabolism is revealed to contribute to therapeutic resistance and pluripotent state. Cancer stem cells (CSCs) rewire cellular metabolism to survive the chemotherapeutics and initiate cancer relapse. However, few studies focus on the effect of GEM on cancer cell metabolism, the stemness status, and the involved mechanisms which are crucial in PanCa treatment. In this study, we demonstrate that GEM treatment induces metabolic reprogramming from mitochondrial oxidation to glycolysis and promotes cancer stem-like status. However, inhibition of glycolysis using 2-deoxy-D-glucose (2-DG) suppresses cancer stemness and strengthens the cytotoxicity of GEM. We further demonstrate that GEM-induced metabolic reprogramming is KRASdependent as knockdown of KRAS reverses the metabolic shift. In addition, GEMinduced metabolic reprogramming activates AMP-activated protein kinase (AMPK) which promotes glycolytic flux and cancer stemness. Our results further reveal the involvement of GEM-induced reactive oxygen species (ROS) in the activation of KRAS/ AMPK pathway in regulation of metabolic reprogramming and cancer stemness, while N-acetyl-L-cysteine (NAC), a ROS scavenger, inhibits the activated KRAS/AMPK pathway, which is further validated by introducing exogenous hydrogen peroxide (H 2 O 2). Collectively, these findings reveal an undesired effect of GEM in PanCa treatment. Therefore, regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming may be effective approaches to eliminate CSCs and enhance chemosensitivity of GEM to improve the prognosis of patients with PanCa.

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“…Besides, CPT1A-suppression or etomoxir treatment fails to maintain redox homeostasis in detached CRC cells and induces sensitivity to glucose deprivation in PDAC cells. 166,190 Further, in gastrointestinal cancer cells, genetic inhibition or pharmacological treatment of CPT2 with perhexiline disrupts NADPH and promotes cell apoptosis after oxaliplatin treatment. Combining perhexiline with oxaliplatin leads to a significant suppression of cancer progression.…”

Section: Fatty Acid Oxidationmentioning

confidence: 99%

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

Lin

Tian

et al. 2020

Sig Transduct Target Ther

267

196

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Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.

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An indispensable role of CPT-1a to survive cancer cells during energy stress through rewiring cancer metabolism

Cited by 20 publications

References 26 publications

Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection

Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection

WITHDRAWN: ROS/KRAS/AMPK signaling determines gemcitabine-induced pancreatic cancer stem-like cell property in vitro

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

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