Metabolic Adaptation Of Cancer Cells Research Articles

Abstract 1784: Glucose metabolism and de novo palmitate synthesis under normoxia and hypoxia in breast cancer cells that preferentially metastasize to lung and liver

Abstract Cancer cells are exposed to variable oxygen and nutrient availability during the metastatic process which can influence metabolic adaptations of cancer cells to metastasize to distant sites. Thus, we investigated the metabolic adaptations of breast cancer cells that preferentially metastasize to lung (metM-WntLung cells; MLg) and liver (metM-WntLiver cells; MLr) in normoxia and hypoxia and at different glucose concentrations. In normoxia, 14C-glucose uptake is similar, but mRNA abundance of hexokinase, the initial rate-limiting step in glycolysis, was 22% higher in MLg cells. This is consistent with higher 13C6-glucose flux into glycolytic metabolites pyruvate (M+3) and lactate (M+3) in MLg compared to MLr. Also, de novo palmitate synthesis from 13C6-glucose was 7.6% higher in MLg and was accompanied by higher mRNA expression of ATP-citrate lyase (ACLY), which converts citrate to acetyl-CoA for fatty acid synthesis. These suggest greater glucose metabolism in MLg compared to MLr in normoxia, consistent with reduced viability of MLr by 39% in high glucose (25 mM) concentrations. Further, mRNA abundance of CPT1A, a rate-limiting step in fatty acid oxidation, is 23% higher in MLg. Moreover, the fatty acid oxidation inhibition (etomoxir) reduced viability of MLg by 26.7% compared to MLr, suggesting that fatty acid synthesis and oxidation are critical for MLg. Protein expression of HIF1α, a transcription factor that induces glycolysis during hypoxia, is 1.5-fold higher in MLr than MLg in normoxia, consistent with higher MLr mRNA abundance of pyruvate dehydrogenase kinase (PDK1), a target of HIF1α that inhibits pyruvate dehydrogenase (PDH) activity. Surprisingly, mRNA abundance of pyruvate carboxylase (PC), the enzyme that converts pyruvate to oxaloacetate, is also higher in MLr (39%) than MLg, thus supporting a potential alternative mechanism for glucose metabolites to enter the TCA cycle in normoxia in MLr. In hypoxia, viability of MLr, relative to MLg, increased by 11% at high glucose concentration. This was accompanied by higher hexokinase (33%) and PDK1 (83%) mRNA abundance suggesting MLr’s shift towards a glycolytic phenotype. However, de novo palmitate synthesis from 13C6-glucose is higher in MLg, suggesting that palmitate synthesis is maintained in MLg even in hypoxia. Altogether, results demonstrate that glucose utilization shifts in breast cancer cells that preferentially metastasize to lung vs liver, but de novo fatty acid synthesis is higher in MLg in different oxygen conditions. Thus, targeting breast cancer cells’ adaptation to glucose and de novo fatty acid synthesis may be a potential strategy to prevent breast cancer progression to distant organs. Citation Format: Marjorie Anne A. Layosa, Morgan Conrad, Stephen Hursting, Dorothy Teegarden. Glucose metabolism and de novo palmitate synthesis under normoxia and hypoxia in breast cancer cells that preferentially metastasize to lung and liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1784.

Abstract 5972: Therapeutic modulation of rock overcomes metabolic adaption to oxphos inhibition and suppresses tumor growth

Abstract Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Previous work in our lab, as well as others, have identified a metabolic vulnerability in targeting oxidative phosphorylation (OXPHOS) in SMARCA4-mutant lung cancer. However, OXPHOS inhibitors are still not approved to treat cancer due to modest efficacy and adverse effects. This strongly suggests that novel, efficacious and tolerated agents that synergize with OXPHOS inhibition are urgently needed. To this end, we undertook a functional genomics screen by utilizing a focused CRISPR-Cas9 library targeting genes with available FDA approved therapeutics in genetically defined lung cancer cell lines. Importantly, we utilized low doses of the OXPHOS inhibitor IACS-10759 that are known to be well tolerated in patients. Among our top validated hits was ROCK1/2 kinases and we demonstrate that Belumasudil, a clinically approved ROCK inhibitor with a robust safety and tolerability profile, displays a synergistic combination with IACS-10759. Furthermore, low doses of IACS-10759 synergized with ROCK inhibition in vivo eliciting marked tumor growth inhibition. Mechanistically, we showed that the combination of Belumasudil and IACS-10759 induced a profound energetic stress. This was primarily due to ROCK inhibition-mediated suppression of the normally observed adaptive increase in glycolysis upon OXPHOS inhibition. Steady-state metabolomics and C13-glucose isotope tracing confirmed downregulation of multiple glycolytic metabolites and reduced glycolytic flux by the combination of ROCK inhibition and IACS-10759 and was associated with severe reduction in glucose uptake. In summary, our study identified a key role of ROCK kinases in metabolic adaptation of cancer cells and provides a strong rationale for pursuing ROCK inhibitors as novel combination agents with OXPHOS inhibition and lay the foundation for future clinical investigation in genetically defined subtypes of lung cancer. Citation Format: Nicholas Blazanin, Xiaobing Liang, Iqbal Mahmud, Eiru Kim, Lin Tan, Nazanin Esmaeili Anvar, Waikin Chan, Min Jin Ha, Rosalba Minelli, Michael Peoples, Philip Lorenzi, Travar Hart, Yonathan Lissanu, Nicholas Blazanin. Therapeutic modulation of rock overcomes metabolic adaption to oxphos inhibition and suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5972.

Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.

The dynamic changes between glycolysis and oxidative phosphorylation (OXPHOS) for adenosine triphosphate (ATP) output, along with glucose, glutamine, and fatty acid utilization, etc., lead to the maintenance and selection of growth advantageous to tumor cell subgroups in an environment of iron starvation and hypoxia. Iron plays an important role in the three major biochemical reactions in nature: photosynthesis, nitrogen fixation, and oxidative respiration, which all require the participation of iron-sulfur proteins, such as ferredoxin, cytochrome b, and the complex I, II, III in the electron transport chain, respectively. Abnormal iron-sulfur cluster synthesis process or hypoxia will directly affect the function of mitochondrial electron transfer and mitochondrial OXPHOS. More research results have indicated that iron metabolism, oxygen availability and hypoxia-inducible factor mutually regulate the shift between glycolysis and OXPHOS. In this article, we make a perspective review to provide novel opinions of the regulation of glycolysis and OXPHOS in tumor cells.

Amino Acid Metabolism in Bone Metastatic Disease.

Breast and prostate tumors frequently metastasize to the bone, but the underlying mechanisms for osteotropism remain elusive. An emerging feature of metastatic progression is metabolic adaptation of cancer cells to new environments. This review will summarize the recent advances on how cancer cells utilize amino acid metabolism during metastasis, from early dissemination to interactions with the bone microenvironment. Recent studies have suggested that certain metabolic preferences for amino acids may be associated with bone metastasis. Once in the bone microenvironment, cancer cells encounter a favorable microenvironment, where a changing nutrient composition of the tumor-bone microenvironment may alter metabolic interactions with bone-resident cells to further drive metastatic outgrowth. Enhanced amino acid metabolic programs are associated with bone metastatic disease and may be further augmented by the bone microenvironment. Additional studies are necessary to fully elucidate the role of amino acid metabolism on bone metastasis.

Metabolic adaptations of cancer in extreme tumor microenvironments.

Cancer cells are highly heterogeneous to adapt to extreme tumor microenvironments (TMEs). TMEs challenge cancer cells via hypoxia, nutrition starvation, and acidic pH, promoting invasion and metastasis concomitant with genetic, epigenetic, and metabolic alterations. Metabolic adaptation to an extreme TME could allow cancer cells to evade cell death and immune responses, as well as resulting in drug resistance, recurrence, and poor patient prognosis. Therefore, elucidation of the metabolic adaptation of malignant cancer cells within TMEs is necessary, however, most are still elusive. Recently, adaptation of cancer cells within the TME can be analyzed via cell-cell interactions at the single-cell level. In addition, information into organelle-organelle interactions has recently been obtained. These cell-cell, and organelle-organelle interactions demonstrate the potential as new cancer therapy targets, as they play essential roles in the metabolic adaptation of cancer cells to the TME. In this manuscript, we review (1) metabolic adaptations within tumor microenvironments through (2) cell-to-cell, and (3) organelle-organelle metabolic interactions.

Modelling cancer metabolism invitro: current improvements and future challenges.

Advances in cancer biology over the past decades have revealed that metabolic adaptation of cancer cells is an essential aspect of tumorigenesis. However, recent insights into tumour metabolism invivo have revealed dissimilarities with results obtained invitro. This is partly due to the reductionism of invitro cancer models that struggle to reproduce the complexity of tumour tissues. This review describes some of the discrepancies in cancer cell metabolism between invitro and invivo conditions, and presents current methodological approaches and tools used to bridge the gap with the clinically relevant microenvironment. As such, these approaches should generate new knowledge that could be more effectively translated into therapeutic opportunities.

Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.

Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success. In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells. The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity. Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Connexins and Glucose Metabolism in Cancer.

Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.

A New Strategy to Fight Metallodrug Resistance: Mitochondria‐Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells

AbstractMetabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein‐based cyclometalated IrIII complex, Ir‐Rhein, that can accurately target mitochondria and effectively inhibit metabolic adaptations. The complex Ir‐Rhein induces severe mitochondrial damage and initiates mitophagy to reduce the number of mitochondria and subsequently inhibit both mitochondrial and glycolytic bioenergetics, which eventually leads to ATP starvation death. Moreover, Ir‐Rhein can overcome cisplatin resistance. Co‐incubation experiment, 3D tumor spheroids experiment and transcriptome analysis reveal that Ir‐Rhein shows promising antiproliferation performance for cisplatin‐resistant cancer cells with the regulation of platinum resistance‐related transporters. To our knowledge, this is a new strategy to overcome metallodrug resistance with a mitochondria‐relevant treatment.

A New Strategy to Fight Metallodrug Resistance: Mitochondria-Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells.

Metabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein-based cyclometalated IrIII complex, Ir-Rhein, that can accurately target mitochondria and effectively inhibit metabolic adaptations. The complex Ir-Rhein induces severe mitochondrial damage and initiates mitophagy to reduce the number of mitochondria and subsequently inhibit both mitochondrial and glycolytic bioenergetics, which eventually leads to ATP starvation death. Moreover, Ir-Rhein can overcome cisplatin resistance. Co-incubation experiment, 3D tumor spheroids experiment and transcriptome analysis reveal that Ir-Rhein shows promising antiproliferation performance for cisplatin-resistant cancer cells with the regulation of platinum resistance-related transporters. To our knowledge, this is a new strategy to overcome metallodrug resistance with a mitochondria-relevant treatment.

The Tumor Suppressor Kinase LKB1: Metabolic Nexus.

Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.

NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation.

Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.

Metabolic Features of Tumor Dormancy: Possible Therapeutic Strategies.

Simple SummaryTumor recurrence still represents a major clinical challenge for cancer patients. Cancer cells may undergo a dormant state for long times before re-emerging. Both intracellular- and extracellular-driven pathways are involved in maintaining the dormant state and the subsequent awakening, with a mechanism that is still mostly unknown. In this scenario, cancer metabolism is emerging as a critical driver of tumor progression and dissemination and have gained increasing attention in cancer research. This review focuses on the metabolic adaptations characterizing the dormant phenotype and supporting tumor re-growth. Deciphering the metabolic adaptation sustaining tumor dormancy may pave the way for novel therapeutic approaches to prevent tumor recurrence based on combined metabolic drugs.Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit.

Understanding the Crosstalk Between Epigenetics and Immunometabolism to Combat Cancer.

The interaction between metabolic and epigenetic events shapes metabolic adaptations of cancer cells and also helps rewire the proliferation and activity of surrounding immune cells in the tumor microenvironment (TME). Recent studies indicate that the TME imposes metabolic constraints on immune cells, inducing them to attain a tolerogenic state, incompetent of mounting effective tumor eradication. Owing to extensive mutations acquired over repeated cell divisions, tumor cells selectively accumulate metabolites that regulate the activity of key epigenetic enzymes to mediate activation/suppression of genes associated with T-cell function and macrophage polarization. Further, multiple modulators connecting epigenetic and metabolic pathways help dictate the preferential induction of cytokines and expression of lineage-specifying genes associated with immunosuppressive T-cell differentiation.In this chapter, we attempt to discuss the mechanisms underpinning the metabolic and epigenetic interplay in immune cells of the TME and how modulating these events can boost the application of existing anticancer immunotherapy.

Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH.

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

ERK signaling controls productive HIF-1 binding to chromatin and cancer cell adaptation to hypoxia through HIF-1α interaction with NPM1.

The hypoxia‐inducible factor HIF‐1 is essential for oxygen homeostasis. Despite its well‐understood oxygen‐dependent expression, regulation of its transcriptional activity remains unclear. We show that phosphorylation by extracellular signal‐regulated kinases1/2 (ERK1/2), in addition to promoting HIF‐1α nuclear accumulation, also enhances its interaction with chromatin and stimulates direct binding to nucleophosmin (NPM1), a histone chaperone and chromatin remodeler. NPM1 is required for phosphorylation‐dependent recruitment of HIF‐1 to hypoxia response elements, its interaction with acetylated histones, and high expression of HIF‐1 target genes under hypoxia. Transcriptome analysis revealed a significant number of hypoxia‐related genes commonly regulated by NPM1 and HIF‐1. These NPM1/HIF‐1α co‐upregulated genes are enriched in three different cancer types, and their expression correlates with hypoxic tumor status and worse patient prognosis. In concert, silencing of NPM1 expression or disruption of its association with HIF‐1α inhibits metabolic adaptation of cancer cells and triggers apoptotic death upon hypoxia. We suggest that ERK‐mediated phosphorylation of HIF‐1α regulates its physical interaction with NPM1, which is essential for the productive association of HIF‐1 with hypoxia target genes and their optimal transcriptional activation, required for survival under low oxygen or tumor growth.

Morpho\u2010metabotyping the oxidative stress response

Oxidative stress and reactive oxygen species (ROS) are central to many physiological and pathophysiological processes. However, due to multiple technical challenges, it is hard to capture a comprehensive readout of the cell, involving both biochemical and functional status. We addressed this problem by developing a fully parallelized workflow for metabolomics (providing absolute quantities for > 100 metabolites including TCA cycle, pentose phosphate pathway, purine metabolism, glutathione metabolism, cysteine and methionine metabolism, glycolysis and gluconeogenesis) and live cell imaging microscopy. The correlative imaging strategy was applied to study morphological and metabolic adaptation of cancer cells upon short-term hydrogen peroxide (H2O2) exposure in vitro. The combination provided rich metabolic information at the endpoint of exposure together with imaging of mitochondrial effects. As a response, superoxide concentrations were elevated with a strong mitochondrial localization, and multi-parametric image analysis revealed a shift towards fragmentation. In line with this, metabolism reflected both the impaired mitochondrial function and shifts to support the first-line cellular defense and compensate for energy loss. The presented workflow combining high-end technologies demonstrates the applicability for the study of short-term oxidative stress, but it can be suitable for the in-depth study of various short-term oxidative and other cellular stress-related phenomena.

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

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.

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells

A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.