Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy

Belič, Aleš; Decock, Julie

doi:10.1002/1878-0261.13024

Cited by 19 publications

(10 citation statements)

References 77 publications

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“…LDH-C was found to be predominantly expressed in the growing testes and spermatozoa ( Rodriguez et al, 2003 ), with no clear relation to cancer pathogenesis. Some reports demonstrated enhanced LDH-C expression in various tumours such as lung, melanoma, kidney, and breast ( Koslowski et al, 2002 ; Kong et al, 2016 ; Hua et al, 2017 ; Chen et al, 2021 ), and being a promising target for cancer therapy ( Thomas et al, 2020 ; Naik and Decock, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

2021

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Background: Lactate dehydrogenase (LDH) plays an important role in cancer pathogenesis and enhanced expression/activity of this enzyme has been correlated with poor prognosis. In this study we determined the expression profile of LDH-A and B in normal as well as in endocrine-resistant and -responsive breast cancer cells and the effect of their knockdown on LDH activity, lactate production, proliferation and cell motility.Methods: Knockdown experiments were performed using siRNA and shRNA. The expression profile of LDH and signaling molecules was determined using PCR and western blotting. Intracellular LDH activity and extracellular lactate levels were measured by a biochemical assay. Cell motility was determined using wound healing, while proliferation was determined using MTT assay.Results: LDH-A was expressed in all of the tested cell lines, while LDH-B was specifically expressed only in normal and endocrine-resistant breast cancer cells. This was correlated with significantly enhanced LDH activity and lactate production in endocrine resistant breast cancer cells when compared to normal or endocrine responsive cancer cells. LDH-A or -B knockdown significantly reduced LDH activity and lactate production, which led to reduced cell motility. Exogenous lactate supplementation enhanced cell motility co-incident with enhanced phosphorylation of ERK1/2 and reduced E-cadherin expression. Also, LDH-A or -B knockdown reduced ERK 1/2 phosphorylation.Conclusion: Enhanced cell motility in endocrine resistant breast cancer cells is at least in part mediated by enhanced extracellular lactate levels, and LDH inhibition might be a promising therapeutic target to inhibit cancer cell motility.

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Section: Introductionmentioning

confidence: 99%

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

2021

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“…A study by Naik [ 115 ] examined whether LDHC is involved in regulating genomic stability and whether it could be targeted to influence the cellular fitness of tumor cells.…”

Section: Resultsmentioning

confidence: 99%

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

et al. 2022

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Male breast cancers are uncommon, as men account for less than 1 percent of all breast carcinomas. Among the predisposing risk factors for male breast cancer, the following appear to be significant: (a) breast/chest radiation exposure, (b) estrogen use, diseases associated with hyper-estrogenism, such as cirrhosis or Klinefelter syndrome, and (c) family health history. Furthermore, there are clear familial tendencies, with a higher incidence among men who have a large number of female relatives with breast cancer and (d) major inheritance susceptibility. Moreover, in families with BRCA mutations, there is an increased risk of male breast cancer, although the risk appears to be greater with inherited BRCA2 mutations than with inherited BRCA1 mutations. Due to diagnostic delays, male breast cancer is more likely to present at an advanced stage. A core biopsy or a fine needle aspiration must be performed to confirm suspicious findings. Infiltrating ductal cancer is the most prevalent form of male breast cancer, while invasive lobular carcinoma is extremely uncommon. Male breast cancer is almost always positive for hormone receptors. A worse prognosis is associated with a more advanced stage at diagnosis for men with breast cancer. Randomized controlled trials which recruit both female and male patients should be developed in order to gain more consistent data on the optimal clinical approach.

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“…Lactate dehydrogenase C ( LDHC ) belongs to the lactate dehydrogenase family of isozymes and is expressed only in the testes (Naik & Decock, 2022). LDHC is essential for lactate metabolism during spermatogenesis, catalysing NADH‐dependent interconversion of lactate and pyruvate.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 17 translocation affects sperm morphology: Two case studies and literature review

Huang

et al. 2022

Andrologia

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We present two cases of infertile males with teratozoospermia stemming from chromosome 17 translocation. The patients present karyotypes that have not been previously reported. Genes located on breakpoints (17p11.2, 9q31, and 11p15) were analysed to find the probable mechanism affecting sperm morphology. Our results suggest that ALKBH5, TOP3A, and LLGL1 interactions may be an underlying cause of abnormal sperm head morphology. Translocation of chromosome 17 occurred in conjunction with chromosome 9 and chromosome 11 translocation in the two cases, resulting in oligozoospermia and asthenozoospermia, respectively. These abnormal phenotypes may involve meiosis-and motility-related genes such as LDHC, DNHD1, UBQLN3, and NUP98. Translocation is thus a risk factor for sperm morphological abnormalities and motility deficiency. The interaction network of 22 genes on breakpoints suggests that they contribute to spermatogenesis as a group. In conclusion, this study highlighted the importance of investigating genes linked to sperm morphology, together with chromosome 17 translocation and reproductive risks. For patients interested in screening before a future pregnancy, we recommend preimplantation genetic diagnosis to reduce the risk of karyotypically unbalanced foetuses and birth defects.

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Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy

Cited by 19 publications

References 77 publications

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

Chromosome 17 translocation affects sperm morphology: Two case studies and literature review

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