Lactic acid, a driver of tumor-stroma interactions

Niu, Dun; Wu, Yiwen; Lei, Ziyao; Zhang, Ming; Xie, Zhizhong; Tang, Shengsong

doi:10.1016/j.intimp.2022.108597

Cited by 20 publications

(12 citation statements)

References 74 publications

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“…It is that closely related to tumor proliferation, anti-apoptosis, chemoresistance, metastasis and poor clinical outcomes. [14,17,18] Furthermore, hyperlactatemia is commonly considered as a surrogate for critical illness severity and associated with increased mortality rates. A large retrospective study of 23,598 intensive care unit (ICU) patient, the total mortality approaching 12.1%.…”

Section: Discussionmentioning

confidence: 99%

Warburg effect secondary to diffuse large B‑cell lymphoma-associated hemophagocytic lymphohistiocytosis: a case report

Zhou

Wang

Zhu

et al. 2022

Preprint

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Background: The increase in glucose consumption during aerobic glycolysis of cancer cells, known as the Warburg effect, is associated with dismal prognosis. Warburg effect secondary to diffuse large B‑cell lymphoma (DLBCL) is rare and there is no specific treatment regimen. Case presentation: We here described a case of patient who presented with hemophagocytic lymphohistiocytosis and developed hyperlactacemia inducing by Warburg effect, then he was successfully treated by continuous renal replacement therapy (CRRT) and diagnostic chemotherapy. Eventually, he was diagnosed as DLBCL. Conclusion: Existing evidence shows that Warburg effect can be secondary to diffuse large B-cell lymphoma, CRRT combined with diagnostic chemotherapy was effective in this case. Additive attention should be paid to this phenomenon and effective strategy remains to be explored.

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Section: Discussionmentioning

confidence: 99%

Warburg effect secondary to diffuse large B‑cell lymphoma-associated hemophagocytic lymphohistiocytosis: a case report

Zhou

Wang

Zhu

et al. 2022

Preprint

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“…As expected, silencing METTL5 significantly reduced glucose uptake and lactate generation. It has been observed that the acidic tumor microenvironment (lower pH) is caused by lactate overproduction, which encourages tumor cells to metastasize [21]. Thus, decreased lactate synthesis limits the formation of acidic tumor microenvironments, as seen by increased medium pH.…”

Section: Mettl5 Enhanced the Warburg Effect In Hcc Cellsmentioning

confidence: 99%

METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

Xia

Zhang

et al. 2023

Cancer Communications

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Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6‐adenosine (METTL5) controls the development of HCC and the Warburg effect. Methods In the current study, quantitative real‐time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione‐S‐transferase pulldown, coimmunoprecipitation, RNA sequencing, non‐targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells. Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c‐Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c‐Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c‐Myc protein and inhibited K48‐linked polyubiquitination of c‐Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c‐Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient‐derived tumor xenograft (PDX) models, adenovirus‐mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX‐bearing mice. Conclusions These findings point to a novel mechanism by which CREB1/P300‐METTL5‐USP5‐c‐Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.

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“…Since tumors are regarded as complex heterogenic tissues with hypoxic areas [ 209 ], the Warburg effect is one of the hallmarks of cancer favoring the suppression of normal oxidative phosphorylation and the adaptation to hypoxia [ 210 ] via upregulating HIF-1 and GLUT expression [ 207 ]. Metabolic products such as lactic acid, originating in tumor cells [ 211 , 212 , 213 ], may promote the spontaneous oxidation of ascorbate to DHA due to pH lowering within the tumor microenvironment [ 32 , 33 ]. Both GLUT-mediated DHA uptake as well as enhanced ascorbate oxidation to DHA may be initiated in the tumor [ 214 ].…”

Section: Dha Transportersmentioning

confidence: 99%

Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer

et al. 2023

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Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.

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Lactic acid, a driver of tumor-stroma interactions

Cited by 20 publications

References 74 publications

Warburg effect secondary to diffuse large B‑cell lymphoma-associated hemophagocytic lymphohistiocytosis: a case report

Warburg effect secondary to diffuse large B‑cell lymphoma-associated hemophagocytic lymphohistiocytosis: a case report

METTL5 stabilizes c‐Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer

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