Platinum (II) Nanofibers as Assembly-driven Inhibitors of Metabolic Adaptation in Cancer Cells

Nanostructure-based functions are omnipresent in biology and essential for the diversity of life. Despite their importance, it is difficult to establish mechanisms that define their bioactivity and rationalize them through synthetic designs. As such, strategies that connect bioactive functions through structure formation are scarce. Herein, we design a near-infrared emitting platinum (II)-tripeptide that undergoes a rearrangement using endogenous H2O2 to rapidly assemble into fibrillar superstructures. The resultant assembly inhibits the metabolism of aggressive metastatic MDA-MB-231 cells and A549 cells at the systemic level by blocking aerobic glycolysis and oxidative phosphorylation, thereby shutting down ATP production. Hence, ATP-dependent actin formation and glucose metabolite-dependent histone deacetylase activity are downregulated, leading to apoptosis. By demonstrating that assembly-driven functions can inhibit broad biological pathways, supramolecular nanostructures could offer the next generation biomedical solutions beyond conventional applications.

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Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Cancers ◽

10.3390/cancers10090337 ◽

2018 ◽

Vol 10 (9) ◽

pp. 337 ◽

Cited By ~ 17

Author(s):

Amruta Nayak ◽

Arvinder Kapur ◽

Lisa Barroilhet ◽

Manish Patankar

Keyword(s):

Ovarian Cancer ◽

Oxidative Phosphorylation ◽

Aerobic Glycolysis ◽

Ovarian Tumors ◽

Metabolic Adaptation ◽

Ovarian Cancer Stem Cells ◽

Critical Control Points ◽

Energy Needs ◽

Oxidative Phosphorylation Pathway ◽

Novel Therapeutic Strategies

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

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Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Cancers ◽

10.3390/cancers12040913 ◽

2020 ◽

Vol 12 (4) ◽

pp. 913 ◽

Cited By ~ 1

Author(s):

Hye-Young Min ◽

Honglan Pei ◽

Seung Yeob Hyun ◽

Hye-Jin Boo ◽

Hyun-Ji Jang ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Anticancer Agent ◽

Aerobic Glycolysis ◽

Cancer Cell Line ◽

Steroidal Saponin ◽

Antitumor Effects ◽

Metabolic Switch ◽

Atp Production

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

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Effects of muscle contraction on cytochrome a,a3 redox state

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.2.790 ◽

1993 ◽

Vol 75 (2) ◽

pp. 790-797 ◽

Cited By ~ 17

Author(s):

F. G. Duhaylongsod ◽

J. A. Griebel ◽

D. S. Bacon ◽

W. G. Wolfe ◽

C. A. Piantadosi

Keyword(s):

Near Infrared ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Muscle Lactate ◽

Atp Production ◽

Oxidation Reduction ◽

Wide Range ◽

Cytochrome Oxidation ◽

O2 Delivery

The relationships among mitochondrial O2 availability, O2 delivery, and lactate formation in exercising skeletal muscle remain unclear. Some data suggest that muscle O2 provision is sufficient at maximal O2 consumption (VO2max) to challenge the concept of a mitochondrial O2 limitation at VO2max. The relationships among VO2, mitochondrial O2 availability, and net lactate production were studied over a wide range of exercise intensities. Using near-infrared spectroscopy, the oxidation-reduction state of cytochrome a,a3 was monitored in the canine gracilis in vivo. Twenty adult dogs were anesthetized with alpha-chloralose, intubated, and mechanically ventilated on room air. Five-minute stimulation periods at rates of 2, 3, 4, 5, 7, 8, 10, or 12 stimuli/s were performed. VO2max generally was achieved at a stimulation rate of 8 stimuli/s; mean VO2max was 0.12 +/- 0.09 (SE) ml.min-1 x g-1. The concentration of oxidized mitochondrial cytochrome a,a3 decreased at all work loads relative to resting state and demonstrated a near-linear relationship with muscle VO2 (r2 = 0.99). Muscle lactate efflux and the lactate-pyruvate ratio also were correlated positively with cytochrome a,a3 reduction, suggesting a common regulatory mechanism coupling the processes of aerobic glycolysis and oxidative phosphorylation. At VO2max, the corresponding cytochrome oxidation was not significantly different from that observed at death. Thus, in the gracilis maximal exercise leads to near-complete reduction of cytochrome a,a3 secondary to deficient O2 provision. We conclude that VO2max is limited primarily by O2 delivery to this muscle and not by other factors limiting mitochondrial ATP production or substrate oxidation.

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HO-1 Modulates Aerobic Glycolysis through LDH in Prostate Cancer Cells

Antioxidants ◽

10.3390/antiox10060966 ◽

2021 ◽

Vol 10 (6) ◽

pp. 966

Author(s):

Florencia Cascardo ◽

Nicolás Anselmino ◽

Alejandra Páez ◽

Estefanía Labanca ◽

Pablo Sanchis ◽

...

Keyword(s):

Prostate Cancer ◽

Aerobic Glycolysis ◽

Heme Oxygenase 1 ◽

Free Survival ◽

Atp Production ◽

Inflammatory Damage ◽

Extracellular Lactate ◽

Cellular Energetics ◽

Lactate Levels

Prostate cancer (PCa) is the second most diagnosed malignancy and the fifth leading cause of cancer associated death in men worldwide. Dysregulation of cellular energetics has become a hallmark of cancer, evidenced by numerous connections between signaling pathways that include oncoproteins and key metabolic enzymes. We previously showed that heme oxygenase 1 (HO-1), a cellular homeostatic regulator counteracting oxidative and inflammatory damage, exhibits anti-tumoral activity in PCa cells, inhibiting cell proliferation, migration, tumor growth and angiogenesis. The aim of this study was to assess the role of HO-1 on the metabolic signature of PCa. After HO-1 pharmacological induction with hemin, PC3 and C4-2B cells exhibited a significantly impaired cellular metabolic rate, reflected by glucose uptake, ATP production, lactate dehydrogenase (LDH) activity and extracellular lactate levels. Further, we undertook a bioinformatics approach to assess the clinical significance of LDHA, LDHB and HMOX1 in PCa, identifying that high LDHA or low LDHB expression was associated with reduced relapse free survival (RFS). Interestingly, the shortest RFS was observed for PCa patients with low HMOX1 and high LDHA, while an improved prognosis was observed for those with high HMOX1 and LDHB. Thus, HO-1 induction causes a shift in the cellular metabolic profile of PCa, leading to a less aggressive phenotype of the disease.

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Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Cells ◽

10.3390/cells10010097 ◽

2021 ◽

Vol 10 (1) ◽

pp. 97

Author(s):

Odeya Marciano ◽

Linoy Mehazri ◽

Sally Shpungin ◽

Alexander Varvak ◽

Eldad Zacksenhaus ◽

...

Keyword(s):

Cancer Cells ◽

Aerobic Glycolysis ◽

Metastatic Cancer ◽

Carcinoma Cells ◽

Metabolic Adaptation ◽

Hypoxic Stress ◽

Lung Carcinoma Cells ◽

Metabolic Role ◽

Highly Sensitive ◽

Anticancer Treatment

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.

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Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages

Nature Communications ◽

10.1038/s41467-020-20315-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yawei Wang ◽

Binlin Tang ◽

Lei Long ◽

Peng Luo ◽

Wei Xiang ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Phosphorylation ◽

Near Infrared ◽

Mitochondrial Metabolism ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages ◽

Inflammatory Activation ◽

Treatment Of Obesity ◽

Pharmaceutical Agents

AbstractPro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

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Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽

10.3390/children8070532 ◽

2021 ◽

Vol 8 (7) ◽

pp. 532

Author(s):

Dorota Wesół-Kucharska ◽

Dariusz Rokicki ◽

Aleksandra Jezela-Stanek

Keyword(s):

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Clinical Picture ◽

Poor Prognosis ◽

Treatment Options ◽

Mitochondrial Diseases ◽

Energy Deficit ◽

Atp Production ◽

Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

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NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress

Cell Death and Disease ◽

10.1038/s41419-020-03383-z ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Michael L. Kamradt ◽

Ji-Ung Jung ◽

Kathryn M. Pflug ◽

Dong W. Lee ◽

Victor Fanniel ◽

...

Keyword(s):

Stress Responses ◽

Glucose Deprivation ◽

Metabolic Adaptation ◽

Mitochondrial Morphology ◽

Atp Production ◽

Tumor Microenvironments ◽

Iκb Kinase ◽

Critical Measure

AbstractCancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK−/− cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM.

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Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells

Cancers ◽

10.3390/cancers13051111 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1111

Author(s):

Pulin Che ◽

Lei Yu ◽

Gregory K. Friedman ◽

Meimei Wang ◽

Xiaoxue Ke ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Focal Adhesion ◽

Aerobic Glycolysis ◽

Integrin Αvβ3 ◽

Metabolic Reprogramming ◽

Migration And Invasion ◽

Metabolic Shift ◽

Mitochondrial Oxidative Phosphorylation ◽

Glioblastoma Cells ◽

Arginine Methyltransferase

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

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Dual Mutations Reveal Interactions Between Components of Oxidative Phosphorylation in Kluyveromyces lactis

Genetics ◽

10.1093/genetics/159.3.929 ◽

2001 ◽

Vol 159 (3) ◽

pp. 929-938

Author(s):

G D Clark-Walker ◽

X J Chen

Keyword(s):

Electron Transport ◽

Oxidative Phosphorylation ◽

Atp Synthase ◽

Kluyveromyces Lactis ◽

Mitochondrial Protein ◽

Proton Pumping ◽

Nuclear Genes ◽

Suppressor Activity ◽

Inner Membrane ◽

Atp Production

Abstract Loss of mtDNA or mitochondrial protein synthesis cannot be tolerated by wild-type Kluyveromyces lactis. The mitochondrial function responsible for ρ0-lethality has been identified by disruption of nuclear genes encoding electron transport and F0-ATP synthase components of oxidative phosphorylation. Sporulation of diploid strains heterozygous for disruptions in genes for the two components of oxidative phosphorylation results in the formation of nonviable spores inferred to contain both disruptions. Lethality of spores is thought to result from absence of a transmembrane potential, ΔΨ, across the mitochondrial inner membrane due to lack of proton pumping by the electron transport chain or reversal of F1F0-ATP synthase. Synergistic lethality, caused by disruption of nuclear genes, or ρ0-lethality can be suppressed by the atp2.1 mutation in the β-subunit of F1-ATPase. Suppression is viewed as occurring by an increased hydrolysis of ATP by mutant F1, allowing sufficient electrogenic exchange by the translocase of ADP in the matrix for ATP in the cytosol to maintain ΔΨ. In addition, lethality of haploid strains with a disruption of AAC encoding the ADP/ATP translocase can be suppressed by atp2.1. In this case suppression is considered to occur by mutant F1 acting in the forward direction to partially uncouple ATP production, thereby stimulating respiration and relieving detrimental hyperpolarization of the inner membrane. Participation of the ADP/ATP translocase in suppression of ρ0-lethality is supported by the observation that disruption of AAC abolishes suppressor activity of atp2.1.

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