Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

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Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽

10.3390/cells10071715 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1715

Author(s):

Macus Hao-Ran Bao ◽

Carmen Chak-Lui Wong

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Resistance ◽

Liver Cancer ◽

Effective Treatment ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Metabolic Reprogramming ◽

Combination Therapies ◽

Low Oxygen ◽

Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

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Hypoxic tumor microenvironment: Implications for cancer therapy

Experimental Biology and Medicine ◽

10.1177/1535370220934038 ◽

2020 ◽

Vol 245 (13) ◽

pp. 1073-1086

Author(s):

Sukanya Roy ◽

Subhashree Kumaravel ◽

Ankith Sharma ◽

Camille L Duran ◽

Kayla J Bayless ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Metabolic Regulation ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Tumor Vasculature ◽

Therapeutic Strategies ◽

Therapeutic Resistance ◽

Low Oxygen ◽

Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

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Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01698-5 ◽

2020 ◽

Vol 39 (1) ◽

Cited By ~ 1

Author(s):

Mingyao Huang ◽

Liang Yang ◽

Xueqiang Peng ◽

Shibo Wei ◽

Qing Fan ◽

...

Keyword(s):

Targeted Therapy ◽

Glucose Metabolism ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Mitochondrial Respiratory Chain ◽

Glycogen Metabolism ◽

Tumour Cells ◽

Metabolic Reprogramming ◽

Organizational Principle

Abstract Molecular oxygen (O2) is a universal electron acceptor that is eventually synthesized into ATP in the mitochondrial respiratory chain of all metazoans. Therefore, hypoxia biology has become an organizational principle of cell evolution, metabolism and pathology. Hypoxia-inducible factor (HIF) mediates tumour cells to produce a series of glucose metabolism adaptations including the regulation of glucose catabolism, glycogen metabolism and the biological oxidation of glucose to hypoxia. Since HIF can regulate the energy metabolism of cancer cells and promote the survival of cancer cells, targeting HIF or HIF mediated metabolic enzymes may become one of the potential treatment methods for cancer. In this review, we summarize the established and recently discovered autonomous molecular mechanisms that can induce cell reprogramming of hypoxic glucose metabolism in tumors and explore opportunities for targeted therapy.

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The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22031171 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1171

Author(s):

Dexter L. Puckett ◽

Mohammed Alquraishi ◽

Winyoo Chowanadisai ◽

Ahmed Bettaieb

Keyword(s):

Cancer Cells ◽

Pyruvate Kinase ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Circular Rnas ◽

Tissue Specific ◽

Cell Progression ◽

Non Coding Rnas ◽

Regulatory Effects

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽

10.3390/metabo11070422 ◽

2021 ◽

Vol 11 (7) ◽

pp. 422

Author(s):

Zhanat Koshenov ◽

Furkan E. Oflaz ◽

Martin Hirtl ◽

Johannes Pilic ◽

Olaf A. Bachkoenig ◽

...

Keyword(s):

Er Stress ◽

Energy Demand ◽

Molecular Mechanisms ◽

High Energy ◽

Human Neuroblastoma Cell ◽

Mitochondrial Bioenergetics ◽

Dependent Manner ◽

Human Neuroblastoma ◽

Sigma 1 Receptor ◽

Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

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Proteomic Analysis Reveals the Participation of Energy- and Stress-Related Proteins in the Response of Pseudomonas putida DOT-T1E to Toluene

Journal of Bacteriology ◽

10.1128/jb.187.17.5937-5945.2005 ◽

2005 ◽

Vol 187 (17) ◽

pp. 5937-5945 ◽

Cited By ~ 131

Author(s):

Ana Segura ◽

Patricia Godoy ◽

Pieter van Dillewijn ◽

Ana Hurtado ◽

Nuria Arroyo ◽

...

Keyword(s):

Pseudomonas Putida ◽

Energy Demand ◽

Cell Metabolism ◽

Sugar Transport ◽

Krebs Cycle ◽

High Energy ◽

Solvent Tolerance ◽

Flight Mass Spectrometry ◽

High Concentrations ◽

Related Proteins

ABSTRACT Pseudomonas putida DOT-T1E is tolerant to toluene and other toxic hydrocarbons through extrusion of the toxic compounds from the cell by means of three efflux pumps, TtgABC, TtgDEF, and TtgGHI. To identify other cellular factors that allow the growth of P. putida DOT-T1E in the presence of high concentrations of toluene, we performed two-dimensional gel analyses of proteins extracted from cultures grown on glucose in the presence and in the absence of the organic solvent. From a total of 531 spots, 134 proteins were observed to be toluene specific. In the absence of toluene, 525 spots were clearly separated and 117 proteins were only present in this condition. Moreover, 35 proteins were induced by at least twofold in the presence of toluene whereas 26 were repressed by at least twofold under these conditions. We reasoned that proteins that were highly induced could play a role in toluene tolerance. These proteins, identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry, were classified into four categories: 1, proteins involved in the catabolism of toluene; 2, proteins involved in the channeling of metabolic intermediates to the Krebs cycle and activation of purine biosynthesis; 3, proteins involved in sugar transport; 4, stress-related proteins. The set of proteins in groups 2 and 3 suggests that the high energy demand required for solvent tolerance is achieved via activation of cell metabolism. The role of chaperones that facilitate the proper folding of newly synthesized proteins under toluene stress conditions was analyzed in further detail. Knockout mutants revealed that CspA, XenA, and Tuf-1 play a role in solvent tolerance in Pseudomonas, although this role is probably not specific to toluene, as indicated by the fact that all mutants grew more slowly than the wild type without toluene.

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The F1Fo-ATPase inhibitor, IF1, is a critical regulator of energy metabolism in cancer cells

Biochemical Society Transactions ◽

10.1042/bst20200742 ◽

2021 ◽

Vol 49 (2) ◽

pp. 815-827

Author(s):

Giancarlo Solaini ◽

Gianluca Sgarbi ◽

Alessandra Baracca

Keyword(s):

Cancer Cells ◽

Atp Synthase ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Endogenous Inhibitor ◽

Atpase Inhibitor ◽

Molecular Action ◽

F1fo Atpase

In the last two decades, IF1, the endogenous inhibitor of the mitochondrial F1Fo-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF1 is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF1 remains elusive. Here, we recall the main features of the mechanism of the action of IF1 when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF1 is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF1 as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF1 as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF1 as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF1 on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF1 in cancer and in developing related anticancer strategies.

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Cardiac responses to hypoxia and reoxygenation in Drosophila

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00164.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. R1347-R1357 ◽

Cited By ~ 9

Author(s):

Rachel Zarndt ◽

Sarah Piloto ◽

Frank L. Powell ◽

Gabriel G. Haddad ◽

Rolf Bodmer ◽

...

Keyword(s):

Cardiac Output ◽

Genetic Model ◽

Heart Function ◽

Acute Hypoxia ◽

Hypoxia Inducible Factor ◽

High Energy ◽

Hypoxic Exposure ◽

Low Oxygen ◽

Cardiac Responses ◽

Organ Systems

An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation.

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Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1

Journal of Experimental Medicine ◽

10.1084/jem.20161066 ◽

2017 ◽

Vol 215 (1) ◽

pp. 51-62 ◽

Cited By ~ 35

Author(s):

Mark Y. Jeng ◽

Philip A. Hull ◽

Mingjian Fei ◽

Hye-Sook Kwon ◽

Chia-Lin Tsou ◽

...

Keyword(s):

T Cells ◽

Molecular Mechanisms ◽

Memory T Cells ◽

Cell Metabolism ◽

Global Gene Expression ◽

Metabolic Reprogramming ◽

Transcriptional Reprogramming ◽

Age Related ◽

Global Gene Expression Profiling ◽

And Function

The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

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Sensitivity to Romidepsin Cytotoxicity Depends on STAT3-Dependent Metabolic Reprogramming of Cancer Cells

Blood ◽

10.1182/blood.v124.21.3599.3599 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3599-3599

Author(s):

Maher Abdul-Hay ◽

Daniel Gough ◽

David Levy

Keyword(s):

Cancer Cells ◽

Tyrosine Phosphorylation ◽

Conflicts Of Interest ◽

Global Analysis ◽

Active Form ◽

Disease Free Survival ◽

Cancer Therapeutics ◽

Serine Phosphorylation ◽

Metabolic Reprogramming ◽

Cytokine Signaling

Abstract Introduction: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and accounts for approximately 80% of cases in this group. Even with the best treatment currently available, there is a very high rate of relapse and mortality. The five-year survival rates are only 24% with relapse rates up to 78%. Accordingly the search for a better understanding of the molecular biology and genetics underlying AML is essential in our quest to find treatments that achieve a better overall survival. Signal transduction and activator of transcription protein 3 (STAT3) has been implicated in many human cancers, including AML; up to 50% of AML patients display enhanced tyrosine phosphorylation of STAT3. Constitutively active STAT3 has also been correlated with shorter disease free survival in AML patients. Accumulating clinical, genetic and biochemical data implicate STAT3 in the majority of human malignancies, indicating that it is essential for tumor initiation and/or maintenance. The best understood tumorigenic activity of STAT3 depends on its tyrosine phosphorylation, mostly due to response to increased secretion of cytokines or mutations in oncogenic tyrosine kinases. However, serine phosphorylation of STAT proteins in the absence of tyrosine phosphorylation or increased cytokine signaling has also been implicated in human leukemias. Moreover, it has recently been found that STAT3 contributes to tumor metabolic reprogramming in a cytokine-independent manner through a novel mitochondrial function that was noted to cause myeloproliferative disease-like in mice models. Methods: We conducted a global analysis of metabolites whose abundance in cancer cells depended on the presence of mitochondrial STAT3, assessed by LC/HPLC coupled to mass spectrometry. This analysis identified glutathione (GSH) levels as being dependent on mitochondrial STAT3, along with multiple intermediaries in the GSH biosynthetic pathway. GSH provides essential reducing capacity in cells and its levels are often elevated in cancer. Romidepsin (Depsipeptide) is an HDAC inhibitor that must be converted to an active form by disulfide reduction via glutathione, originally characterized for its cytotoxicity against Ras-transformed cells. We have found enhanced Romidepsin toxicity in STAT3-containing cancer cells, which correlates with the presence of increased GSH and reduced reactive oxygen species (ROS). We found that the enzymes in the GSH synthetic pathway are coordinately regulated by STAT3. We also found that Romidepsin increases STAT3 expression at both the mRNA and the protein levels and we are analyzing the mechanism by which STAT3 is affected by Romidepsin. Conclusion: Enhanced Romidepsin toxicity was found in STAT3-containing cancer cells. These STAT3-containinng cells were noted to have higher glutathione synthase expression, which plays a major role in the GSH production in the gamma glutamyl cycle. This could potentially explain the higher GSH levels noted in the presence of STAT3-contianing cells. These studies hopefully will aid in the design of cancer therapeutics that target STAT3-dependent processes that contribute to oncogenesis and could lead to have better treatments available in myeloid diseases. Disclosures No relevant conflicts of interest to declare.

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