High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

Fiorillo, Marco; Ózsvári, Béla; Sotgia, Federica; Lisanti, Michael P.

doi:10.3389/fonc.2021.740720

Cited by 49 publications

(54 citation statements)

References 87 publications

(103 reference statements)

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“…In the OXPHOS phenotype, higher OCR is linked to higher cellular energy production [ 43 ]. Therefore, to further confirm that the induction of radioresistance in GBM cells is associated with a switch to the OXPHOS phenotype, we examined the rate of ATP production in each cell line.…”

Section: Resultsmentioning

confidence: 99%

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Oliva¹,

Ali²,

Flor³

et al. 2022

CST

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Glioblastoma (GBM) is a fatal disease with recurrences often associated with radioresistance. Although often effective at treating newly diagnosed GBM, increasing evidence suggests that radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness. Using isogenic radiosensitive and radioresistant GBM cell lines and patient-derived xenolines, we found that acquired radioresistance is associated with a shift from a glycolytic metabolism to a more oxidative metabolism marked by a substantial increase in the activity of the mitochondrial res-piratory chain complex cytochrome c oxidase (CcO). This elevated CcO ac-tivity was associated with a switch in the isoform expression of the CcO regulatory subunit COX4, from COX4-2 to COX4-1, assembly of CcO-containing mitochondrial supercomplexes (SCs), and reduced superoxide (O2●-) production. Overexpression of COX4-1 in the radiosensitive cells was sufficient to promote the switch from glycolytic to oxidative metabolism and the incorporation of CcO into SCs, with a concomitant reduction in O2●- production. Conversely, silencing of COX4-1 expression in normally radiore-sistant cells reduced CcO activity, promoted the disassembly of mitochon-drial SCs, and increased O2●- production. Additionally, gain or loss of COX4-1 expression was sufficient to induce the radioresistant or radiosensitive phenotype, respectively. Our results demonstrate that COX4-1 promotes SC assembly in GBM cells, and SC assembly may in turn regulate the pro-duction of reactive oxygen species and thus the acquisition of radiore-sistance in GBM.

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Section: Resultsmentioning

confidence: 99%

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Oliva¹,

Ali²,

Flor³

et al. 2022

CST

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“…Mitochondrial ATP production has been a therapeutic target for cancer treatment for many years 25 . Cancer cells with high ATP levels are aggressive and exhibit multidrug resistance, invasiveness, and spontaneous metastasis.…”

Section: Cancer Metabolism In Metastatic Cellsmentioning

confidence: 99%

“…Active mitochondrial function and cell differentiation can reduce cell type evolution (heterogeneity), inhibit drug resistance, and prevent cancer initiation. However, in tumor cells mitochondrial reprogramming 5,15,24–28 or constitutive activation of intracellular kinase signaling or both 7,29–33 may promote metastatic progression. Therefore, inhibition of these pathways may restrict tumor cell proliferation or promote cell death through feedback inhibition of respiratory capacity, increased ROS, and lower glucose utilization.…”

Section: Introductionmentioning

confidence: 99%

Targeting mitochondrial metabolism for metastatic cancer therapy

Passaniti

Kim

Polster

et al. 2022

Molecular Carcinogenesis

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Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function‐selective extracellular signal‐regulated kinase‐1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.

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“…To date, numerous drugs have been proposed to modulate different functions of mitochondria for tumour therapy, which have been reviewed elsewhere ( 68 , 69 ). Briefly, these strategies aim to compensate alterations in all relevant mitochondrial activities, i.e.…”

Section: Mitochondria Dysfunction In Cancer: Minimal Integrity Pointmentioning

confidence: 99%

“…Briefly, these strategies aim to compensate alterations in all relevant mitochondrial activities, i.e. bioenergetics, signaling, and biosynthetic functions ( 68 , 69 ). At present, most drugs have been tested for antitumour activity in clinical trials ( 68 ).…”

Section: Mitochondria Dysfunction In Cancer: Minimal Integrity Pointmentioning

confidence: 99%

Mitochondria dysfunction in circulating tumor cells

Agnoletto

Volinia

2022

Front. Oncol.

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Circulating tumor cells (CTCs) represent a subset of heterogeneous cells, which, once released from a tumor site, have the potential to give rise to metastasis in secondary sites. Recent research focused on the attempt to detect and characterize these rare cells in the circulation, and advancements in defining their molecular profile have been reported in diverse tumor species, with potential implications for clinical applications. Of note, metabolic alterations, involving mitochondria, have been implicated in the metastatic process, as key determinants in the transition of tumor cells to a mesenchymal or stemness-like phenotype, in drug resistance, and in induction of apoptosis. This review aimed to briefly analyse the most recent knowledge relative to mitochondria dysfunction in CTCs, and to envision implications of altered mitochondria in CTCs for a potential utility in clinics.

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High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

Cited by 49 publications

References 87 publications

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

COX4-1 promotes mitochondrial supercomplex assembly and limits reactive oxide species production in radioresistant GBM

Targeting mitochondrial metabolism for metastatic cancer therapy

Mitochondria dysfunction in circulating tumor cells

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