Mitochondrial and metabolic alterations in cancer cells

Gregorio, Jacopo Di; Petricca, Sabrina; Iorio, Roberto; Toniato, E; Flati, Vincenzo

doi:10.1016/j.ejcb.2022.151225

Cited by 34 publications

(19 citation statements)

References 300 publications

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“…S 3 A). Consistent with previous studies [ 24 ], we found that the TCA cycle and FAO were inhibited while accompanied by enhanced glycolysis (Fig. 3 E), which may briefly indicate a homeostatic mechanism for ATP generation due to the lack of oxygen.…”

Section: Resultssupporting

confidence: 93%

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Fang

Sun

Leng

et al. 2023

J Exp Clin Cancer Res

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Background Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application and the underlying mechanisms at play remain unclear. The aims of this study were to elucidate the role of abnormal signal transmission and metabolism in the chemoresistance of OSCC under hypoxia and to identify targeted drugs that enhance the sensitivity of DDP chemotherapy. Methods Upregulated genes in OSCC were determined by RNA sequencing (RNA-seq), the Cancer Genome Atlas (TCGA) database, immunohistochemistry (IHC), real-time quantitative PCR (RT-qPCR), and western blotting (WB). The clinicopathological significance of insulin-like growth factor-I receptor (IGF1R), argininosuccinate synthetase 1 (ASS1), and pyrroline-5-carboxylate reductase 1 (PYCR1) in OSCC was analysed using tissue micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP-resistance role of IGF1R, ASS1, and PYCR1 in OSCC was investigated in vitro and in vivo. Results Generally, tumour cells exist in a hypoxic microenvironment. By genomic profiling, we determined that IGF1R, as a receptor tyrosine kinase (RTK), was upregulated in OSCC under low-oxygen conditions. Clinically, enhanced IGF1R expression was associated with higher tumour stages and a poorer prognosis in OSCC patients, and its inhibitor, linsitinib, showed synergistic effects with DDP therapy in vivo and in vitro. Since oxygen-deprivation frequently lead to metabolic reprogramming, we further learned via metabolomics analysis that abnormal IGF1R pathways promoted the expression of metabolic enzymes ASS1 and PYCR1 by the transcriptional activity of c-MYC. In detail, enhanced expression of ASS1 promotes arginine metabolism for biological anabolism, whereas PYCR1 activates proline metabolism for redox balance, which maintains the proliferation ability of OSCC cells during DDP treatment under hypoxic conditions. Conclusion Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under hypoxia. Linsitinib targeting IGF1R signaling may lead to promising combination therapy options for OSCC patients with DDP resistance.

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Section: Resultssupporting

confidence: 93%

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Fang

Sun

Leng

et al. 2023

J Exp Clin Cancer Res

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“…However, glucose utilization and carbon sources in cancer are much more heterogeneous than initially thought. Indeed, new studies have revealed a dual capacity of cancer cells to use both glycolytic and oxidative metabolism to sustain ATP production [ 46 ]. In addition, tumours sharing the same clinical diagnosis can show mitochondrial metabolic heterogeneity using glutamine or fatty acids as alternative oxidizable substrates [ 47 ].…”

Section: Mitochondrial Overview In Cancermentioning

confidence: 99%

Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

Rasmo

Cormio

et al. 2023

IJMS

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Ovarian cancer (OC) represents the main cause of death from gynecological malignancies in western countries. Altered cellular and mitochondrial metabolism are considered hallmarks in cancer disease. Several mitochondrial aspects have been found altered in OC, such as the oxidative phosphorylation system, oxidative stress and mitochondrial dynamics. Mitochondrial dynamics includes cristae remodeling, fusion, and fission processes forming a dynamic mitochondrial network. Alteration of mitochondrial dynamics is associated with metabolic change in tumour development and, in particular, the mitochondrial shaping proteins appear also to be responsible for the chemosensitivity and/or chemoresistance in OC. In this review a focus on the mitochondrial dynamics in OC cells is presented.

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“…Interestingly, similar to macrophages, dendritic cells, and cancer cells, M1/M2 transition requires significant changes in metabolic pathways [ 207 , 208 , 209 ]. In this regard, mitochondrial metabolism governs and regulates microglial responses through a phenomenon that has been termed immunometabolism [ 210 , 211 ].…”

Section: Neuroprotective Potential Of β-Caryophyllene and Carnosic Ac...mentioning

confidence: 99%

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

2022

Self Cite

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Inflammation and oxidative stress are interlinked and interdependent processes involved in many chronic diseases, including neurodegeneration, diabetes, cardiovascular diseases, and cancer. Therefore, targeting inflammatory pathways may represent a potential therapeutic strategy. Emerging evidence indicates that many phytochemicals extracted from edible plants have the potential to ameliorate the disease phenotypes. In this scenario, ß-caryophyllene (BCP), a bicyclic sesquiterpene, and carnosic acid (CA), an ortho-diphenolic diterpene, were demonstrated to exhibit anti-inflammatory, and antioxidant activities, as well as neuroprotective and mitoprotective effects in different in vitro and in vivo models. BCP essentially promotes its effects by acting as a selective agonist and allosteric modulator of cannabinoid type-2 receptor (CB2R). CA is a pro-electrophilic compound that, in response to oxidation, is converted to its electrophilic form. This can interact and activate the Keap1/Nrf2/ARE transcription pathway, triggering the synthesis of endogenous antioxidant “phase 2” enzymes. However, given the nature of its chemical structure, CA also exhibits direct antioxidant effects. BCP and CA can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Findings from different in vitro/in vivo experimental models of Parkinson’s disease and Alzheimer’s disease reported the beneficial effects of both compounds, suggesting that their use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

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Mitochondrial and metabolic alterations in cancer cells

Cited by 34 publications

References 300 publications

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Ovarian Cancer: A Landscape of Mitochondria with Emphasis on Mitochondrial Dynamics

Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation

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