scholarly journals Reciprocal regulation of LOXL2 and HIF1α drives the Warburg effect to support pancreatic cancer aggressiveness

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Rongkun Li ◽  
Hengchao Li ◽  
Lili Zhu ◽  
Xiaoxin Zhang ◽  
Dejun Liu ◽  
...  

AbstractHypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. In this study, we identify that lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in PDAC. LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop exists between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. Moreover, LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Collectively, our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.

2021 ◽  
Author(s):  
Rongkun Li ◽  
Yahui Wang ◽  
Lili Zhu ◽  
Xiaoxin Zhang ◽  
Dejun Liu ◽  
...  

Abstract Background Hypoxic microenvironment is common in solid tumors, particularly in pancreatic ductal adenocarcinoma (PDAC). The Warburg effect is known to facilitate cancer aggressiveness and has long been linked to hypoxia, yet the underlying mechanism remains largely unknown. Methods The expression pattern and prognostic value of LOXL2 was analyzed by immunohistochemistry. The effects of LOXL2 on cancer cell proliferation, migration, and invasion in vitro, tumor growth and metastasis in vivo were investigated by genetic manipulation of LOXL2 expression in human PDAC cell lines. The effects of LOXL2 on aerobic glycolysis were examined by glucose uptake, lactate production, and Seahorse Flux Analyzer. Quantitative real-time PCR, western blotting, immunofluorescence and other techniques were conducted to identify molecular mechanism. Results Lysyl oxidase-like 2 (LOXL2) is a hypoxia-responsive gene and is essential for the Warburg effect in pancreatic ductal adenocarcinoma (PDAC). LOXL2 stabilizes hypoxia-inducible factor 1α (HIF1α) from prolyl hydroxylase (PHD)-dependent hydroxylation via hydrogen peroxide generation, thereby facilitating the transcription of multiple glycolytic genes. Therefore, a positive feedback loop is existed between LOXL2 and HIF1α that facilitates glycolytic metabolism under hypoxia. LOXL2 couples the Warburg effect to tumor growth and metastasis in PDAC. Hijacking glycolysis largely compromises LOXL2-induced oncogenic activities. Conclusion Our results identify a hitherto unknown hypoxia-LOXL2-HIF1α axis in regulating the Warburg effect and provide an intriguing drug target for PDAC therapy.


2020 ◽  
Vol 36 (8) ◽  
pp. 580-590
Author(s):  
Rui Wang ◽  
Sheng-Yuan Wang ◽  
Yue Wang ◽  
Rui Xin ◽  
Bing Xia ◽  
...  

Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.


2018 ◽  
Vol 18 (6) ◽  
pp. 454-466 ◽  
Author(s):  
Yunli Shi ◽  
Shengnan Liu ◽  
Shabir Ahmad ◽  
Qingzhi Gao

Increased glycolysis has been one of the metabolic characteristics known as the Warburg effect. The functional and therapeutic importance of the Warburg effect in targeted therapy is scientifically recognized and the glucose metabolic pathway has become a desirable target of anticancer strategies. Glucose transporters (GLUTs) play an important role in cancer glycolysis to sustain cancer cell proliferation, metastasis and survival. Utilizing the knowledge of differential expression and biological functions of GLUTs offers us the possibility of designing and delivering chemotherapeutics toward targeted tumor tissues for improved cancer selectivity. Inhibition of glucose uptake or glycolysis may effectively kill hypoxic cancer cells. Facilitative drug uptake via active transportation provides the potential opportunity to circumvent the drug resistance in chemotherapy. GLUTs as the hallmarks and biotargets of cancer metabolism enable the design and development of novel targeted theranostic agents. In this updated review, we examine the current scenario of the GLUTs as strategic targets in cancer and the unique concepts for discovery and development of GLUTs-targeted anticancer agents. We highlight the recent progresses on structural biology and underlying mechanism studies of GLUTs, with a brief introduction to the computational approaches in GLUT-mediated drug transport and tumor targeting.


2014 ◽  
Vol 53 (1) ◽  
pp. 88-100 ◽  
Author(s):  
Fan Yang ◽  
Huafeng Zhang ◽  
Yide Mei ◽  
Mian Wu

2020 ◽  
Author(s):  
Vasanthakumar Natesan

At present, there is no treatment option available for COVID-19 condition and most importantly the underlying pathophysiology in COVID-19 is not known. No theory at present explains all the clinical features in COVID-19. In this article, I had proposed a hypothesis that explains the underlying pathophysiology in COVID-19 and based on it proposed treatment options for COVID-19. I propose that the adrenergic storm-induced Warburg effect (aerobic glycolysis) may be the underlying mechanism in the COVID-19 condition. I propose alpha1 adrenergic blockers in the early phase and beta-adrenergic blockers in the late phase of COVID-19 to inhibit the adrenergic storm and reverse the Warburg effect in COVID-19 condition.


2019 ◽  
Vol 20 (2) ◽  
pp. 238 ◽  
Author(s):  
Ayako Nagao ◽  
Minoru Kobayashi ◽  
Sho Koyasu ◽  
Christalle C. T. Chow ◽  
Hiroshi Harada

Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.


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