Identification of human LDHC4 as a potential target for anticancer drug discovery

Tan, Hong Kee; Wang, Huali; Ma, Jinhu; Deng, Hui; He, Qinghua; Chen, Qiang; Zhang, Qinglian

doi:10.1016/j.apsb.2021.12.002

Cited by 4 publications

(4 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Malfunction of L-LDHs can lead to abnormal accumulation of L-lactate, which is associated with various diseases including L-lactic acidosis and cancers 1 , 2 , 9 , 16 . High serum L-LDH levels are typically related to poor prognosis in many types of cancers and thus are considered as an indicator of tumor burden and metastasis as well as a complex biomarker pertinent to the activation of several oncogenic signaling pathways 1 , 2 , 16 , 21 , 22 . So far, the structures, functions and catalytic mechanisms of LDHA, LDHB, and LDHC have been well elucidated and their relationships to various diseases especially cancers are under active scrutiny 1 , 2 , 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis

Jin,

Chen,

Yang

et al. 2023

Nat Commun

View full text Add to dashboard Cite

Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient LDHD activity. Here, we perform a systematic biochemical study of mouse LDHD (mLDHD) and determine the crystal structures of mLDHD in FAD-bound form and in complexes with FAD, Mn2+ and a series of substrates or products. We demonstrate that mLDHD is an Mn2+-dependent general dehydrogenase which exhibits catalytic activity for D-lactate and other D-2-hydroxyacids containing hydrophobic moieties, but no activity for their L-isomers or D-2-hydroxyacids containing hydrophilic moieties. The substrate-binding site contains a positively charged pocket to bind the common glycolate moiety and a hydrophobic pocket with some elasticity to bind the varied hydrophobic moieties of substrates. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of LDHD, and the functional roles of mutations in the pathogenesis of D-lactic acidosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis

Jin,

Chen,

Yang

et al. 2023

Nat Commun

View full text Add to dashboard Cite

show abstract

“… 166 LDHC has been shown to promote tumor growth and metastasis of lung adenocarcinomas via activation of the PI3K/Akt/GSK-3β oncogenic-signaling pathway. 18 , 167 We previously demonstrated that LDHC is an immunogenic antigen and plays a role in maintaining genomic stability and mitotic fidelity in breast cancer cell lines, safekeeping tumor cellular fitness. 17 , 168 More specifically, we showed that silencing LDHC results in DNA damage accumulation, microtubule destabilization, mitotic slippage, increased polyploidy and aberrant mitosis, ultimately reducing long-term tumor cell survival.…”

Section: Genomic Integrity-regulatory Ctasmentioning

confidence: 99%

Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer

Naik,

Lattab,

Qasem

et al. 2024

Molecular Therapy: Oncology

View full text Add to dashboard Cite

“…Although it was originally assumed that LDHC was strictly present in the testes, several studies have been published that LDHC is present in a range of cancer tissues, including lung cancer (47%), melanoma (44%), breast cancer (35%), and some prostate cancers [ 95 ]. Identification of LDHC as a potential target for anticancer drug discovery has only recently been addressed with (ethylamino)(oxo)acetic acid showing selective inhibition of LDHC in comparison to LDHA or LDHB [ 96 ].…”

Section: Lactate Dehydrogenasementioning

confidence: 99%

Revisiting the Warburg Effect with Focus on Lactate

Kociánová

Piatrikova

Golias

2022

Cancers

View full text Add to dashboard Cite

Rewired metabolism is acknowledged as one of the drivers of tumor growth. As a result, aerobic glycolysis, or the Warburg effect, is a feature of many cancers. Increased glucose uptake and glycolysis provide intermediates for anabolic reactions necessary for cancer cell proliferation while contributing sufficient energy. However, the accompanying increased lactate production, seemingly wasting glucose carbon, was originally explained only by the need to regenerate NAD+ for successive rounds of glycolysis by the lactate dehydrogenase (LDH) reaction in the cytosol. After the discovery of a mitochondrial LDH isoform, lactate oxidation entered the picture, and lactate was recognized as an important oxidative fuel. It has also been revealed that lactate serves a variety of signaling functions and helps cells adapt to the new environment. Here, we discuss recent findings on lactate metabolism and signaling in cancer while attempting to explain why the Warburg effect is adopted by cancer cells.

show abstract

Identification of human LDHC4 as a potential target for anticancer drug discovery

Cited by 4 publications

References 46 publications

Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis

Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis

Cancer testis antigens: Emerging therapeutic targets leveraging genomic instability in cancer

Revisiting the Warburg Effect with Focus on Lactate

Contact Info

Product

Resources

About