The impact of mitochondria on cancer treatment resistance

Merwe, Michelle van der; Niekerk, Gustav van; Fourie, C.M.T.; Plessis, Manisha du; Engelbrecht, Anna‐Mart

doi:10.1007/s13402-021-00623-y

Cited by 17 publications

(12 citation statements)

References 143 publications

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“…Compared to other disease models, fumarate accumulation was already associated with upregulation of the Nrf2 pathway, oxidative stress in tumour cells, cell senescence, and glucolipotoxicity [23][24][25]. Inevitably, mitochondrial activity and glucose-dependent ROS turnover were affected [23][24][25].…”

Section: Discussionmentioning

confidence: 92%

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4

Stratmann

Eggers

Mattern

et al. 2022

IJMS

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An oversupply of nutrients with a loss of metabolic flexibility and subsequent cardiac dysfunction are hallmarks of diabetic cardiomyopathy. Even if excess substrate is offered, the heart suffers energy depletion as metabolic fluxes are diminished. To study the effects of a high glucose supply, a stably glucose transporter type 4 (GLUT4)-overexpressing cell line presenting an onset of diabetic cardiomyopathy-like phenotype was established. Long-term hyperglycaemia effects were analysed. Rat cardiomyoblasts overexpressing GLUT4 (H9C2KE2) were cultured under normo- and hyperglycaemic conditions for long-term. Expression profiles of several proteins were compared to non-transfected H9C2 cells (H9C2) using RT-qPCR, proteomics-based analysis, or Western blotting. GLUT4 surface analysis, glucose uptake, and cell morphology changes as well as apoptosis/necrosis measurements were performed using flow cytometry. Additionally, brain natriuretic peptide (BNP) levels, reactive oxygen species (ROS) formation, glucose consumption, and lactate production were quantified. Long-term hyperglycaemia in H9C2KE2 cells induced increased GLUT4 presence on the cell surface and was associated with exaggerated glucose influx and lactate production. On the metabolic level, hyperglycaemia affected the tricarboxylic acid (TCA) cycle with accumulation of fumarate. This was associated with increased BNP-levels, oxidative stress, and lower antioxidant response, resulting in pronounced apoptosis and necrosis. Chronic glucose overload in cardiomyoblasts induced by GLUT4 overexpression and hyperglycaemia resulted in metabolically stimulated proteome profile changes and metabolic alterations on the TCA level.

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Section: Discussionmentioning

confidence: 92%

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4

Stratmann

Eggers

Mattern

et al. 2022

IJMS

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“…Despite considerable advances in cancer treatment, cancer recurrence is frequently seen. It has been reported in 50% of patients with soft-tissue sarcoma, 85% of patients with ovarian cancer, and almost all patients with glioblastoma [ 110 ]. Cancer cells can develop resistance to the available treatments through specific genetic and epigenetic changes.…”

Section: Discussionmentioning

confidence: 99%

Targeted Anti-Mitochondrial Therapy: The Future of Oncology

Taghizadeh‐Hesary

Akbari

Bahadori

et al. 2022

Genes

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Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

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“…We further report that TMZ-resistant cells are more oxidative and equipped with fitter mitochondria than TMZ-sensitive cells. This would provide a protective advantage against TMZ-induced cell death in a similar way as it accounts for an acquired resistance to other alkylating agents [ 25 , 27 , 39 , 40 ]. Indeed, similar to other alkylating agents, TMZ is a mitochondrial poison that decreased mtOCR and the mtDNA/nDNA ratio in GBM cells.…”

Section: Discussionmentioning

confidence: 99%

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

Zampieri

Sboarina

Cacace

et al. 2021

IJMS

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Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.

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The impact of mitochondria on cancer treatment resistance

Cited by 17 publications

References 143 publications

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4

Targeted Anti-Mitochondrial Therapy: The Future of Oncology

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

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