SLC16 Family: From Atomic Structure to Human Disease.

The solute carrier 16 (SLC16) family represents a diverse group of membrane proteins mediating the transport of monocarboxylates across biological membranes. Family members show a variety of functional roles ranging from nutrient transport and intracellular pH regulation to thyroid hormone homeostasis. Changes in the expression levels and transport function of certain SLC16 transporters are manifested in severe health disorders including cancer, diabetes, and neurological disorders. L-Lactate-transporting SLC16 family members play essential roles in the metabolism of certain tumors and became validated drug targets. This review illuminates the SLC16 family under a new light using structural information obtained from a SLC16 homolog. Furthermore, the role of these transporters in cancer metabolism and how their inhibition can contribute to anticancer therapy are discussed.

Caveolin-1 in oncogenic metabolic symbiosis.

Metabolic phenotypes of cancer cells are heterogeneous and flexible as a tumor mass is a hurriedly evolving system capable of constant adaptation to oxygen and nutrient availability. The exact type of cancer metabolism arises from the combined effects of factors intrinsic to the cancer cells and factors proposed by the tumor microenvironment. As a result, a condition termed oncogenic metabolic symbiosis in which components of the tumor microenvironment (TME) promote tumor growth often occurs. Understanding how oncogenic metabolic symbiosis emerges and evolves is crucial for perceiving tumorigenesis. The process by which tumor cells reprogram their TME involves many mechanisms, including changes in intercellular communication, alterations in metabolic phenotypes of TME cells, and rearrangement of the extracellular matrix. It is possible that one molecule with a pleiotropic effect such as Caveolin-1 may affect many of these pathways. Here, we discuss the significance of Caveolin-1 in establishing metabolic symbiosis in TME.

Recycling the Interspecific Relations with Epithelial Cells: Bacteria and Cancer Metabolic Symbiosis.

Several aspects of the human physiology are controlled by the microbiota that plays a key role in health and disease. In fact, microbial dysbiosis is associated with numerous diseases, including several types of cancer such as colon, gastric, esophageal, pancreatic, laryngeal, breast and gallbladder carcinomas.Metabolic symbiosis between non-malignant cells and the resident microbita is crucial for the host homeostasis. However, cancer cells are able to repurpose the pre-existing metabolic symbiosis, being able to recycle those relations and also create novel metabolic symbiosis, leading to profound alterations on the local microenvironment.In here we will explore some of these symbiotic metabolic interactions between bacteria and non-malignant cells in two different contexts: colon and uterine cervix. The way malignant cells are able to recycle these normal interactions and also create novel types of symbiotic metabolic relations will also be discussed.The knowledge of these complex interactions and recycling mechanisms is of extreme importance for cancer treatment, as new therapeutic targets could be developed.

Metabolism in the Tumor Microenvironment.

From a general perspective, in the context of solid tumors, we can distinguish metabolic alterations of cancer cells from those of the stroma. These two components interact with each other and with the extracellular matrix (ECM), and these interactions can take the form of either metabolic competition or metabolic symbiosis. The aim of this chapter is to overview the canonical metabolic alterations of tumor and stroma cells and to present specific examples of metabolic competition and symbiosis. We will also discuss the complexity and plasticity of metabolism, which pose indeed a serious threat to our ability to target selective metabolic features of tumor microenvironment with drugs. Finally, we will highlight some limitations of state-of-the-art techniques used to study tumor metabolism and propose some innovative solutions to investigate the clinical relevance of metabolic alterations for patient management and treatment.

Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [13C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [13C] can also be used to evaluate tumor metabolism and to follow the efficiency of a treatment at a preclinical or clinical stage. Relevant descriptors of tumor metabolism are now required to better stratify patients for the development of personalized metabolic medicine. In this review, we discuss the current limitations in basic research and drug discovery in the field of cancer metabolism to foster the need for more clinically relevant target identification and validation. We discuss the design of adapted drug screening assays and compound efficacy evaluation methods for the discovery of innovative anti-cancer therapeutic approaches at the level of tumor energetics. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Metabolic plasticity in heterogeneous pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignant neoplasms. The recognized hallmarks of PDA are regarded to be downstream events of metabolic reprogramming. Because PDA is a heterogeneous disease that is influenced by genetic polymorphisms and changes in the microenvironment, metabolic plasticity is a novel feature of PDA. As intrinsic factors for metabolic plasticity, K-ras activation and mutations in other tumor suppressor genes induce abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. As extrinsic factors, the acidic and oxygen/nutrient-deprived microenvironment also induces cancer cells to reprogram their metabolic pathway and hijack stromal cells (mainly cancer-associated fibroblasts and immunocytes) to communicate, thereby adapting to metabolic stress. Therefore, a better understanding of the metabolic features of PDA will contribute to the development of novel diagnostic and therapeutic strategies.

STAT3:FOXM1 and MCT1 drive uterine cervix carcinoma fitness to a lactate-rich microenvironment.

Uterine cervix cancer is the second most common malignancy in women worldwide with human papillomavirus (HPV) as the etiologic factor. The two main histological variants, squamous cell carcinomas (SCC) and adenocarcinomas (AC), resemble the cell morphology of exocervix and endocervix, respectively. Cancer metabolism is a cancer hallmark conditioned by the microenvironment. As uterine cervix homeostasis is dependent on lactate, we hypothesized lactate plays a role in uterine cervix cancer progression. Using in vitro (SiHa-SCC and HeLa-AC) and BALB-c/SCID models, we demonstrated that lactate metabolism is linked to histological types, with SCC predominantly consuming and AC producing lactate. MCT1 is a key factor, allowing lactate consumption and being regulated in vitro by lactate through the FOXM1:STAT3 pathway. In vivo models showed that SCC (SiHa) expresses MCT1 and is dependent on lactate to grow, whereas AC (HeLa) expresses MCT1 and MCT4, with higher growth capacities. Immunohistochemical analysis of tissue microarrays (TMA) from human cervical tumors showed that MCT1 expression associates with the SCC type and metastatic behavior of AC, whereas MCT4 expression concomitantly increases from in situ SCC to invasive SCC and is significantly associated with the AC type. Consistently, FOXM1 expression is statistically associated with MCT1 positivity in SCC, whereas the expression of FOXO3a, a FOXM1 functional antagonist, is linked to MCT1 negativity in AC. Our study reinforces the role of the microenvironment in the metabolic adaptation of cancer cells, showing that cells that retain metabolic features of their normal counterparts are positively selected by the organ's microenvironment and will survive. In particular, MCT1 was shown to be a key element in uterine cervix cancer development; however, further studies are needed to validate MCT1 as a suitable therapeutic target in uterine cervix cancer.

Adipose tissue and adipocytes support tumorigenesis and metastasis.

Adipose tissue influences tumor development in two major ways. First, obese individuals have a higher risk of developing certain cancers (endometrial, esophageal, and renal cell cancer). However, the risk of developing other cancers (melanoma, rectal, and ovarian) is not altered by body mass. In obesity, hypertrophied adipose tissue depots are characterized by a state of low grade inflammation. In this activated state, adipocytes and inflammatory cells secrete adipokines and cytokines which are known to promote tumor development. In addition, the adipocyte mediated conversion of androgens to estrogen specifically contributes to the development of endometrial cancer, which shows the greatest relative risk (6.3-fold) increase between lean and obese individuals. Second, many tumor types (gastric, breast, colon, renal, and ovarian) grow in the anatomical vicinity of adipose tissue. During their interaction with cancer cells, adipocytes dedifferentiate into pre-adipocytes or are reprogrammed into cancer-associated adipocytes (CAA). CAA secrete adipokines which stimulate the adhesion, migration, and invasion of tumor cells. Cancer cells and CAA also engage in a dynamic exchange of metabolites. Specifically, CAA release fatty acids through lipolysis which are then transferred to cancer cells and used for energy production through ß-oxidation. The abundant availability of lipids from adipocytes in the tumor microenvironment, supports tumor progression and uncontrolled growth. Given that adipocytes are a major source of adipokines and energy for the cancer cell, understanding the mechanisms of metabolic symbiosis between cancer cells and adipocytes, should reveal new therapeutic possibilities. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

The emerging role of lactate in tumor microenvironment and its clinical relevance.

In recent years, the significant impact of lactate in the tumor microenvironment has been greatly documented. Acting not only as an energy substance in tumor metabolism, lactate is also an imperative signaling molecule. It plays key roles in metabolic remodeling, protein lactylation, immunosuppression, drug resistance, epigenetics and tumor metastasis, which has a tight relation with cancer patients' poor prognosis. This review illustrates the roles lactate plays in different aspects of tumor progression and drug resistance. From the comprehensive effects that lactate has on tumor metabolism and tumor immunity, the therapeutic targets related to it are expected to bring new hope for cancer therapy.

Mitochondrial transfer in tunneling nanotubes-a new target for cancer therapy.

A century ago, the Warburg effect was first proposed, revealing that cancer cells predominantly rely on glycolysis during the process of tumorigenesis, even in the presence of abundant oxygen, shifting the main pathway of energy metabolism from the tricarboxylic acid cycle to aerobic glycolysis. Recent studies have unveiled the dynamic transfer of mitochondria within the tumor microenvironment, not only between tumor cells but also between tumor cells and stromal cells, immune cells, and others. In this review, we explore the pathways and mechanisms of mitochondrial transfer within the tumor microenvironment, as well as how these transfer activities promote tumor aggressiveness, chemotherapy resistance, and immune evasion. Further, we discuss the research progress and potential clinical significance targeting these phenomena. We also highlight the therapeutic potential of targeting intercellular mitochondrial transfer as a future anti-cancer strategy and enhancing cell-mediated immunotherapy.

H2S-Powered Nanomotors for Active Therapy of Tumors by Inducing Ferroptosis and Lactate-Pyruvate Axis Disorders.

Disruption of the symbiosis of extra/intratumoral metabolism is a good strategy for treating tumors that shuttle resources from the tumor microenvironment. Here, we report a precision treatment strategy for enhancing pyruvic acid and intratumoral acidosis to destroy tumoral metabolic symbiosis to eliminate tumors; this approach is based on PEGylated gold and lactate oxidase-modified aminated dendritic mesoporous silica with lonidamine and ferrous sulfide loading (PEG-Au@DMSNs/FeS/LND@LOX). In the tumor microenvironment, LOX oxidizes lactic acid to produce pyruvate, which represses tumor cell proliferation by inhibiting histone gene expression and induces ferroptosis by partial histone monoubiquitination. In acidic tumor conditions, the nanoparticles release H2S gas and Fe2+ ions, which can inhibit catalase activity to promote the Fenton reaction of Fe2+, resulting in massive ·OH production and ferroptosis via Fe3+. More interestingly, the combination of H2S and LND (a monocarboxylic acid transporter inhibitor) can cause intracellular acidosis by lactate, and protons overaccumulate in cells. Multiple intracellular acidosis is caused by lactate-pyruvate axis disorders. Moreover, H2S provides motive power to intensify the shuttling of nanoparticles in the tumor region. The findings confirm that this nanomedicine system can enable precise antitumor effects by disrupting extra/intratumoral metabolic symbiosis and inducing ferroptosis and represents a promising active drug delivery system candidate for tumor treatment.

How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.

Fibroblast-epithelial metabolic coupling in laryngeal cancer.

OBJECTIVES: To explore the Fibroblast-epithelial metabolic coupling among laryngeal cancers and its prognostic roles METHODS: We reviewed the clinical information of patients with laryngeal cancer in our department. Paraffin-embedded tissues from included patients were immune-stained with antibodies towards MCT4 and TOMM20 and evaluated for stromal and epithelial expression. Survival analysis and Cox regression analysis were applied to investigate the prognostic factor of laryngeal squamous cell carcinoma. TCGA database was used to validate our result. RESULTS: Stromal MCT4 and TOMM20 were both significantly associated with each other among laryngeal cancer tissues. High expression of both Stromal MCT4 and TOMM20 is related to poor prognosis in laryngeal cancer. Stromal MCT4 expression was an independent prognostic indicator for laryngeal cancer. Furthermore, cancer cell MCT4 expression has no relationship with the clinical characteristics of laryngeal cancer. CONCLUSIONS: Our results support that the phenomenon of metabolic symbiosis was exist in the laryngeal cancer tissue. In addition, TOMM20 and stromal MCT4 could be used as new therapeutic targets for laryngeal cancer.

Metabolic tricks of cancer cells.

One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.

Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells.

Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells.

There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.

Metabolic Symbiosis in Chemoresistance: Refocusing the Role of Aerobic Glycolysis.

Cellular metabolic reprogramming is now recognized as a hallmark of tumors. Altered tumor metabolism determines the malignant biological behaviors and phenotypes of cancer. More recently, studies have begun to reveal that cancer cells generally exhibit increased glycolysis or oxidative phosphorylation (OXPHOS) for Adenosine Triphosphate(ATP)generation, which is frequently associated with drug resistance. The metabolism of drug-resistant cells is regulated by the PI3K/AKT/mTOR pathway which ultimately confer cancer cells drug resistance phenotype. The key enzymes involved in glycolysis and the key molecules in relevant pathways have been used as targets to reverse drug resistance. In this review, we highlight our current understanding of the role of metabolic symbiosis in therapeutic resistance and discuss the ongoing effort to develop metabolic inhibitors as anti-cancer drugs to overcome drug resistance to classical chemotherapy.

GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH-1 expression.

Cancer stem cells play critical roles in tumor initiation, progression, and relapse. Since we previously found that GATA6 promotes the stemness in HCT-116 and HT-29 human colorectal cancer (CRC) cells, we aimed to identify the downstream mediator(s) of the stemness-stimulating effect of GATA6 herein. LRH-1 was found as a direct target of GATA6 and its upregulation promoted the stemness in both HCT-116 and HT-29 cells. Subsequently, hypoxia-inducible factor-1α (HIF-1α) was identified as a direct target of LRH-1 and its expression level and activity were significantly elevated in the LRH-1-overexpressing clones established from the aforementioned two CRC lines. Accordingly, the expression levels of several HIF-1α targets were also markedly increased, resulting in a stronger glycolysis associated with dramatic elevations of the lactate levels in these cells. Strikingly, higher mitochondrial activities were also found in these clones which might be attributed to the increase of PGC-1α stimulated by the lactate uptaken through the upregulated MCT-1. Finally, significant increases in the self-renewal ability, intracellular radical oxygen species levels and mitochondrial mass were detected in the CD133+ /CD44+ subpopulations isolated from CRC cells regardless of their LRH-1 expression levels. Together, our results suggest a novel metabolic symbiosis between different colorectal cancer stem cell subpopulations critical for maintaining their mutual stemness.

Monocarboxylate transporters in cancer.

BACKGROUND: Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway. SCOPE OF REVIEW: Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81. MAJOR CONCLUSIONS: Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT+/- and MCT-/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

Lactic Acidosis in the Presence of Glucose Diminishes Warburg Effect in Lung Adenocarcinoma Cells.

Lactic acidosis (3 to 40 mM, pH < 6.9) is a condition found in solid tumors because tumor cells have a high rate of glucose consumption and lactate production even in the presence of oxygen; nevertheless, the microenvironment might still provide a sufficient glucose supply. Lactic acidosis has been proposed to shift metabolism from aerobic glycolysis toward oxidative phosphorylation (OXPHOS). We tested if lung tumor cells cultured under lactic acidosis shift their metabolism from glycolysis to OXPHOS by consuming extracellular lactate, increasing growth rate. We analyzed lung adenocarcinoma (A-549, A-427) cell lines and non-transformed fibroblast cells (MRC-5), which were cultured using RPMI-1640 medium initially containing lactate (2 mM) and glucose (10 mM), at pH 7.2 or 6.2 and oxygen tension 21% O2 (normoxia) or 2% O2 (hypoxia). We obtained growth curves, as well as glucose consumption and lactate production rates (measured during exponential growth) for each cell line. HIF-1α (Hypoxia-inducible factor 1 α), CS (citrate synthase) and AMPK (AMP-activated protein kinase) transcript levels were analyzed using RT-qPCR. By flow cytometry, we determined: (a) expression of glucose transporters (GLUT)1 and 4; (b) lactate transporters (MCT)1 and 4; (c) cell cycle profile, and (d) protein levels of HIF-1α, total and phosphorylated AMPK (pAMPK). Mitochondrial functionality was evaluated by measuring O2 consumption in tumor cells using polarography and a Clark-type electrode. Tumor and non-transformed cells used both aerobic glycolysis and OXPHOS for obtaining energy. As of 48 h of culture, lactate levels ranged from (4.5-14 mM), thus forming a lactic environment. Lactic acidosis diminished GLUT1/GLUT4 expression and glucose consumption in A-549, but not in A-427 cells, and induced differential expression of HIF-1α, AMPK, and CS transcripts. A-427 cells increased pAMPK and HIF-1α levels and shifted their metabolism increasing OXPHOS; thus supporting cell growth. Conversely, A-549 cells increased HIF-1α protein levels, but did not activate AMPK and diminished OXPHOS. A-549 cells survived by arresting cells in G1-phase. Our findings show that lactic acidosis diminishes Warburg effect in tumor cells, but this change does not necessarily promote a shift to OXPHOS. Hence, lung adenocarcinomas show a differential metabolic response even when they are under the same microenvironmental conditions.