The role of mitochondrial fission in cardiovascular health and disease.
Nature reviews. Cardiology
Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
10.1038/s41569-022-00703-y
Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.
Neuron
Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.
10.1016/j.neuron.2022.03.015
Understanding the Warburg effect: the metabolic requirements of cell proliferation.
Science (New York, N.Y.)
In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
10.1126/science.1160809
Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
Cell death & disease
The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.
10.1038/s41419-022-04917-3
Glucose Starvation-Induced Rapid Death of Nrf1-Deficient, but Not Nrf2-Deficient, Hepatoma Cells Results from Its Fatal Defects in the Redox Metabolism Reprogramming.
Zhu Yu-Ping,Zheng Ze,Xiang Yuancai,Zhang Yiguo
Oxidative medicine and cellular longevity
Metabolic reprogramming exists in a variety of cancer cells, with the most relevance to glucose as a source of energy and carbon for survival and proliferation. Of note, Nrf1 was shown to be essential for regulating glycolysis pathway, but it is unknown whether it plays a role in cancer metabolic reprogramming, particularly in response to glucose starvation. Herein, we discover that hepatoma cells are sensitive to rapid death induced by glucose deprivation, such cell death appears to be rescued by interference, but HepG2 (wild-type, ) or cells are roughly unaffected by glucose starvation. Further evidence revealed that cell death is resulted from severe oxidative stress arising from aberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation of cells, as also accompanied by weakened pentose phosphate pathway, dysfunction of serine-to-glutathione synthesis, and accumulation of reactive oxygen species (ROS) and damages, such that the intracellular GSH and NADPH were exhausted. These demonstrate that glucose starvation leads to acute death of , rather than , cells resulting from its fatal defects in the redox metabolism reprogramming. This is owing to distinct requirements of Nrf1 and Nrf2 for regulating the constructive and inducible expression of key genes involved in redox metabolic reprogramming by glucose deprivation. Altogether, this work substantiates the preventive and therapeutic strategies against -deficient cancer by limiting its glucose and energy demands.
10.1155/2020/4959821
Nuclear Respiratory Factor 1 Overexpression Inhibits Proliferation and Migration of PC3 Prostate Cancer Cells.
Cancer genomics & proteomics
BACKGROUND/AIM:The role of nuclear respiratory factor 1 (NRF1) on the prostate cancer progression is controversial. We aimed to investigate the effect of NRF1 overexpression on the metastasis potential of PC3 prostate cancer cells and the associated molecular mechanisms. MATERIALS AND METHODS:Cell survival, migration capacity, mitochondrial biogenesis, the expression of TGF-β signaling and EMT markers were examined after overexpression and silencing of NRF1 in PC3 cells. RESULTS:We found that NRF1-overexpressing cells exhibited a decreased cell viability and proliferation ability as well as a reduced migration capacity compared to control cells. Moreover, ectopic expression of NRF1 increased the mitochondrial biogenesis and inhibited the EMT characteristics, including a decrease in the mesenchymal marker, α-SMA and an increase in the epithelial cell marker, E-cadherin. We also demonstrated that overexpression of NRF1 suppressed the expression of TGF-β signaling in PC3 cells. As expected, silencing of NRF1 reversed the abovementioned effects. CONCLUSION:This study demonstrated that upregulation of NRF1 holds the potential to inhibit the metastasis of prostate cancer, possibly through an elevation of mitochondrial biogenesis and the subsequent repression of TGF-β-associated EMT. Therapeutic avenues that increase NRF1 expression may serve as an adjunct to conventional treatments of prostate cancer.
10.21873/cgp.20346
Nuclear Respiratory Factor 1 (NRF1) Transcriptional Activity-Driven Gene Signature Association with Severity of Astrocytoma and Poor Prognosis of Glioblastoma.
Bhawe Kaumudi,Felty Quentin,Yoo Changwon,Ehtesham Nasreen Z,Hasnain Seyed E,Singh Varindera Paul,Mohapatra Ishani,Roy Deodutta
Molecular neurobiology
Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM. NRF1 has higher mRNA expression and transcription factor activity in astrocytoma compared to non-tumor brain tissue. NRF1 activity also correlated with the aggressiveness of cancer. Increased NRF1 TF activity coupled with overexpression of RHOG was associated with poor survival of GBM patients. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition and cell cycle progression. Overexpression of CDK4, AKT1, APAF1, HDAC1, NBN, TGFB1, & TNFRSF1A and downregulation of CASP3, IL7, STXBP1 and OPA1 predicted GBM malignancy in high expressors of NRF1 activity. Increased expression of the NRF1 motif containing genes, H6PD, NAT10, NBEAL2, and RNF19B predicted poor survival of IDH1 wild-type GBM patients. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets - LDHA, ZMAT3, NSUN2, ARMC5, NDEL1, CLPTM1L, ALKBH5, YIPF5, PPP2CA, and TFG. These findings suggest that aberrant NRF1 activity may contribute to the pathogenesis of GBM and severity of astrocytoma. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.
10.1007/s12035-020-01979-2
Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.
Xu Ke,Yin Na,Peng Min,Stamatiades Efstathios G,Shyu Amy,Li Peng,Zhang Xian,Do Mytrang H,Wang Zhaoquan,Capistrano Kristelle J,Chou Chun,Levine Andrew G,Rudensky Alexander Y,Li Ming O
Science (New York, N.Y.)
Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8 T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.
10.1126/science.abb2683
Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses.
Immunity
Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4Ldha mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4Ldha mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.
10.1016/j.immuni.2021.04.008
NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer.
Journal of experimental & clinical cancer research : CR
BACKGROUND:NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated. METHODS:Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms. RESULTS:NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle. CONCLUSIONS:Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.
10.1186/s13046-022-02412-3
Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition.
Boudreau Aaron,Purkey Hans E,Hitz Anna,Robarge Kirk,Peterson David,Labadie Sharada,Kwong Mandy,Hong Rebecca,Gao Min,Del Nagro Christopher,Pusapati Raju,Ma Shuguang,Salphati Laurent,Pang Jodie,Zhou Aihe,Lai Tommy,Li Yingjie,Chen Zhongguo,Wei Binqing,Yen Ivana,Sideris Steve,McCleland Mark,Firestein Ron,Corson Laura,Vanderbilt Alex,Williams Simon,Daemen Anneleen,Belvin Marcia,Eigenbrot Charles,Jackson Peter K,Malek Shiva,Hatzivassiliou Georgia,Sampath Deepak,Evangelista Marie,O'Brien Thomas
Nature chemical biology
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.
10.1038/nchembio.2143
Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.
Oncogene
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.
10.1038/onc.2017.6
LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma.
Zhao Juping,Huang Xin,Xu Zhaoping,Dai Jun,He Hongchao,Zhu Yu,Wang Haofei
Molecular medicine reports
Previous studies have indicated that high expression of lactate dehydrogenase A (LDHA) exists in many human cancers. Recently, several reports showed that silencing or inhibition of LDHA could suppress metastasis of human cancer including renal cell carcinoma (RCC). However, the mechanism remains unknown. The role of LDHA in RCC migration and invasion was investigated using immunohistochemistry, western blotting, Transwell and scratch assays, and in vivo experiment. The influence of LDHA on the Warburg effect was also investigated by LDHA activity and lactate production assay. LDHA was overexpressed in RCC tissues and predicted a worse survival following renal resection. Correlation analysis demonstrated that LDHA was negatively correlated with E‑cadherin and positively with N‑cadherin. Experimentally, both in vivo and in vitro experiments found downregulation of LDHA suppressed RCC cells migration and invasion by inhibiting EMT. In addition, results indicated LDHA could promote the Warburg effect. Further research presented that the LDHA inhibitor, oxamate, suppressed tumor metastasis by inhibiting LDHA activity and EMT. These results demonstrated that LDHA mediates tumor metastasis by promoting EMT in RCC, suggesting that LDHA could be a promising therapeutic target for RCC therapy.
10.3892/mmr.2017.7637
POU1F1 transcription factor induces metabolic reprogramming and breast cancer progression via LDHA regulation.
Oncogene
Metabolic reprogramming is considered hallmarks of cancer. Aerobic glycolysis in tumors cells has been well-known for almost a century, but specific factors that regulate lactate generation and the effects of lactate in both cancer cells and stroma are not yet well understood. In the present study using breast cancer cell lines, human primary cultures of breast tumors, and immune deficient murine models, we demonstrate that the POU1F1 transcription factor is functionally and clinically related to both metabolic reprogramming in breast cancer cells and fibroblasts activation. Mechanistically, we demonstrate that POU1F1 transcriptionally regulates the lactate dehydrogenase A (LDHA) gene. LDHA catalyzes pyruvate into lactate instead of leading into the tricarboxylic acid cycle. Lactate increases breast cancer cell proliferation, migration, and invasion. In addition, it activates normal-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs). Conversely, LDHA knockdown in breast cancer cells that overexpress POU1F1 decreases tumor volume and [F]FDG uptake in tumor xenografts of mice. Clinically, POU1F1 and LDHA expression correlate with relapse- and metastasis-free survival. Our data indicate that POU1F1 induces a metabolic reprogramming through LDHA regulation in human breast tumor cells, modifying the phenotype of both cancer cells and fibroblasts to promote cancer progression.
10.1038/s41388-021-01740-6
LDHA Promotes Oral Squamous Cell Carcinoma Progression Through Facilitating Glycolysis and Epithelial-Mesenchymal Transition.
Cai Hongshi,Li Jiaxin,Zhang Yadong,Liao Yan,Zhu Yue,Wang Cheng,Hou Jinsong
Frontiers in oncology
Aerobic glycolysis is the main pathway for energy metabolism in cancer cells. It provides energy and biosynthetic substances for tumor progression and metastasis by increasing lactate production. Lactate dehydrogenase A (LDHA) promotes glycolysis process by catalyzing the conversion of pyruvate to lactate. Despite LDHA exhibiting carcinogenesis in various cancers, its role in oral squamous cell carcinoma (OSCC) remains unclear. This study demonstrated that LDHA was over-expressed in both OSCC tissues and cell lines, and was significantly associated with lower overall survival rates in patients with OSCC. Using weighted gene correlation network analysis and gene set enrichment analysis for the gene expression data of patients with OSCC (obtained from The Cancer Genome Atlas database), a close association was identified between epithelial-mesenchymal transition (EMT) and LDHA in promoting OSCC progression. The knockdown of LDHA suppressed EMT, cell proliferation, and migration and invasion of OSCC cells . Moreover, the silencing of LDHA inhibited tumor growth . Oxamate, as a competitive LDHA inhibitor, was also suppressed diverse malignant biocharacteristics of OSCC cells. Our findings reveal that LDHA acts as an oncogene to promote malignant progression of OSCC by facilitating glycolysis and EMT, and LDHA may be a potential anticancer therapeutic target.
10.3389/fonc.2019.01446
E2F1-Induced FTH1P3 Promoted Cell Viability and Glycolysis Through miR-377-3p/LDHA Axis in Laryngeal Squamous Cell Carcinoma.
Cancer biotherapy & radiopharmaceuticals
Laryngeal squamous cell carcinoma (LSCC) has poor prognosis, and the mechanism underlying the pathogenesis of LSCC remains unclear. Recently, a study has shown that long nonprotein coding RNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) plays a crucial role in tumor pathogenesis. This study explored the potential role of FTH1P3 in LSCC. The expression of E2F1 and FTH1P3 in LSCC was analyzed by quantitative real time-polymerase chain reaction assay. The direct targets of FTH1P3 and miR-377-3p were predicted, followed by functional validation. The functional role of FTH1P3 was investigated in AMC-HN-8 and TU686 cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and the measurement of glucose uptake and L-lactate production. The results showed that overexpression of FTH1P3 promoted cell viability and glycolysis in LSCC cells, but knockdown of FTH1P3 suppressed this behavior. Upregulated FTH1P3 was associated with increased E2F1 expression in LSCC patients. E2F1 was proved to induce FTH1P3 expression in LSCC cells. FTH1P3 modulated miR-377-3p expression by targeting miR-377-3p. Interestingly, LDHA was identified to be a target of miR-377-3p, and FTH1P3 promoted LDHA expression by suppressing miR-377-3p. In addition, knockdown of FTH1P3 mitigated E2F1-induced cell viability and glycolysis through miR-377-3p/LDHA in AMC-HN-8 cells. More importantly, knockdown of E2F1 inhibited tumor growth and FTH1P3 expression . In conclusion, these findings revealed that E2F1-induced FTH1P3 promoted cell viability and glycolysis through miR-377-3p/LDHA axis in LSCC, which could provide a promising novel strategy for LSCC treatment.
10.1089/cbr.2020.4266
Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia.
Yu Haizhi,Yin Yafei,Yi Yifang,Cheng Zhao,Kuang Wenyong,Li Ruijuan,Zhong Haiying,Cui Yajuan,Yuan Lingli,Gong Fanjie,Wang Zhihua,Li Heng,Peng Hongling,Zhang Guangsen
Cancer communications (London, England)
BACKGROUND:T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T-ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T-ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene-targeting treatment on T-ALL and the underlying molecular mechanism. METHODS:Primary T-ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T-ALL cells. Quantitative real-time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T-ALL cells were treated with oxamate. A T-ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene-editing technology, and then TUNEL, Western blotting, and T-ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T-ALL transgenic zebrafish. RESULTS:Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P < 0.001). Blocking LDHA significantly decreased the gene and protein expression of c-Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK-3β) in the phosphatidylinositol 3'-kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down-regulated c-Myc mRNA and protein expression in T-ALL transgenic zebrafish. CONCLUSION:Targeting LDHA exerted an antileukemic effect on T-ALL, representing a potential strategy for T-ALL treatment.
10.1002/cac2.12080
PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA.
OncoTargets and therapy
BACKGROUND:Suppressed gluconeogenesis and increased glycolysis are common in clear cell renal cell carcinoma (ccRCC). Phosphoenolpyruvate carboxykinase 1 (PCK1) is a rate-limiting gluconeogenesis enzyme. However, the role of PCK1 in tumor metabolism and progression remains unclear. METHODS:Artificial modulation of PCK1 (down- and upregulation) in two ccRCC cell lines was performed to explore the role of PCK1 in the glycolytic phenotype and in tumor growth and metastasis in vitro and in vivo. Sixty-two patients with ccRCC underwent F-fluorodeoxyglucose (F-FDG) positron emission tomography. The levels of PCK1 and lactate dehydrogenase A (LDHA) in ccRCC tissues and peritumor tissues were investigated with immunohistochemistry. The relationships between F-FDG accumulation and the expression of PCK1 and LDHA were analyzed. The mechanisms underlying the regulation of LDHA by PCK1 were analyzed using in vitro molecular techniques. RESULTS:PCK1 suppressed ccRCC cell growth and metastasis in vitro and inhibited tumorigenesis in nude mice by blocking the aerobic glycolysis pathway. Clinically, low levels of PCK1 expression were associated with poor prognosis in patients with ccRCC. The expression level of PCK1 was negatively correlated with tumor progression, the LDHA expression level and F-FDG accumulation in primary ccRCC tissue. We also demonstrated that PCK1 reduces the stability of LDHA through posttranslational regulation. Finally, we showed that the effects of PCK1 on glucose metabolism, cell proliferation and metastasis are mediated via the inhibition of LDHA. CONCLUSION:Our study identified a novel molecular mechanism underlying the Warburg effect. PCK1 may serve as a candidate prognostic biomarker, and targeting the PCK1/LDHA pathway might be a new strategy to selectively inhibit tumor metabolism in human ccRCC.
10.2147/OTT.S241717