Metabolic rewiring in drug resistant cells exhibit higher OXPHOS and fatty acids as preferred major source to cellular energetics

Salunkhe, Sameer; Mishra, Saket V.; Ghorai, Atanu; Hole, Aarti; Chandrani, Pratik; Dutt, Amit; Chilakapati, Murali; Dutt, Shilpee

doi:10.1016/j.bbabio.2020.148300

Cited by 30 publications

(25 citation statements)

References 15 publications

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“…To date, the study of OXPHOS represents a major interest to understand not only the mitochondrial dependency of AML cells [ 12 , 18 , 19 , 20 , 21 , 22 ] but also their adaptive nongenetic mechanisms of resistance to anticancer treatments such as intensive chemotherapy [ 13 , 23 , 24 ] or the newly approved targeted therapies IDHi and venetoclax [ 25 , 26 , 27 , 28 , 29 , 30 ]. In this context, the assessment of a standardized, easy, fast, and robust protocol to measure mitochondrial oxygen consumption in blasts is an urgent need to define whether OXPHOS activity might be a functional biomarker that is predictive of drug response as proposed in Bosc et al, in press [ 30 ] and support future clinical trials for AML management.…”

Section: Discussionmentioning

confidence: 99%

Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients

Fovez

Laine

Goursaud

et al. 2021

Cancers

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Resistant acute myeloid leukemia (AML) exhibits mitochondrial energy metabolism changes compared to newly diagnosed AML. This phenotype is often observed by evaluating the mitochondrial oxygen consumption of blasts, but most of the oximetry protocols were established from leukemia cell lines without validation on primary leukemia cells. Moreover, the cultures and storage conditions of blasts freshly extracted from patient blood or bone marrow cause stress, which must be evaluated before determining oxidative phosphorylation (OXPHOS). Herein, we evaluated different conditions to measure the oxygen consumption of blasts using extracellular flow analyzers. We first determined the minimum number of blasts required to measure OXPHOS. Next, we compared the OXPHOS of blasts cultured for 3 h and 18 h after collection and found that to maintain metabolic organization for 18 h, cytokine supplementation is necessary. Cytokines are also needed when measuring OXPHOS in cryopreserved, thawed and recultured blasts. Next, the concentrations of respiratory chain inhibitors and uncoupler FCCP were established. We found that the FCCP concentration required to reach the maximal respiration of blasts varied depending on the patient sample analyzed. These protocols provided can be used in future clinical studies to evaluate OXPHOS as a biomarker and assess the efficacy of treatments targeting mitochondria.

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Section: Discussionmentioning

confidence: 99%

Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients

Fovez

Laine

Goursaud

et al. 2021

Cancers

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“…More specifically, the metabolic plasticity of AraC and mitoxantrone residual cells was assessed, highlighting that mitochondrial metabolism was fed by FAs. In light of this, these drugs were tested in combination with etomoxir, disclosing a useful mechanism of chemosensitization [136,137]. A similar mechanism has been identified in residual breast cancer cells responsible for tumor recurrence, because they show a metabolic shift, with increased FA transport into mitochondria and high ROS levels.…”

Section: The Other Side Of the Coin: The Pro-tumor Effects Of Ros Produced By Boosted Faomentioning

confidence: 95%

“…This aspect is useful to increase the sensitivity to other drugs, including etomoxir. [136,137] Vitamin C/E Breast cancer…”

Section: Skq1mentioning

confidence: 99%

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison

Castelli

Falco

Ciccarone

et al. 2021

Cancers

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Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

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“…Enhanced, accelerated aerobic glycolysis has been shown to be responsible for resistance against various cancer drugs including sorafenib [ 529 ], palbociclib [ 530 ], oxaliplatin [ 531 ], doxorubicin [ 532 ], lapatinib [ 533 ] paclitaxel [ 534 ], bevacizumab [ 535 ], and cetuximab [ 536 ]. However, recent studies also revealed that many cancers such as myeloid leukemia [ 537 ], non-Hodgkin’s lymphoma [ 538 ], pancreatic ductal adenocarcinoma [ 539 ], melanoma [ 540 ], and high-grade prostate cancers [ 541 ] do not have impaired mitochondrial OXPHOS [ 542 ] while aggressive and drug-resistant cancers may actually upregulate mitochondrial oxidative phosphorylation (OXPHOS) as part of their defense mechanisms [ 543 , 544 , 545 ] to enhance autophagy [ 546 ], increase stemness [ 547 ], or remodel OXPHOS metabolism to promote survival [ 541 , 548 ].…”

Section: Melatonin May Promote Prp Physiological Functions and Inhibi...mentioning

confidence: 99%

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

Loh¹,

Reíter

2022

Molecules

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The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.

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Metabolic rewiring in drug resistant cells exhibit higher OXPHOS and fatty acids as preferred major source to cellular energetics

Cited by 30 publications

References 15 publications

Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients

Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

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