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Lactate Dehydrogenase-A (LDH-A) Preserves Cancer Stemness and Recruitment of Tumor-Associated Macrophages to Promote Breast Cancer Progression.

ABSTRACT: Increasing evidence reveals that breast cancer stem cells (BCSCs) subtypes with distinct properties are regulated by their abnormal metabolic changes; however, the specific molecular mechanism and its relationship with tumor microenvironment (TME) are not clear. In this study, we explored the mechanism of lactate dehydrogenase A (LDHA), a crucial glycolytic enzyme, in maintaining cancer stemness and BCSCs plasticity, and promoting the interaction of BCSCs with tumor associated macrophages (TAMs). Firstly, the expression of LDHA in breast cancer tissues was much higher than that in adjacent tissues and correlated with the clinical progression and prognosis of breast cancer patients based on The Cancer Genome Atlas (TCGA) data set. Moreover, the orthotopic tumor growth and pulmonary metastasis were remarkable inhibited in mice inoculated with 4T1-shLdha cells. Secondly, the properties of cancer stemness were significantly suppressed in MDA-MB-231-shLDHA or A549-shLDHA cancer cells, including the decrease of ALDH⁺ cells proportion, the repression of sphere formation and cellular migration, and the reduction of stemness genes (SOX2, OCT4, and NANOG) expression. However, the proportion of ALDH⁺ cells (epithelial-like BCSCs, E-BCSCs) was increased and the proportion of CD44⁺ CD24^- cells (mesenchyme-like BCSCs, M-BCSCs) was decreased after LDHA silencing, suggesting a regulatory role of LDHA in E-BCSCs/M-BCSCs transformation in mouse breast cancer cells. Thirdly, the expression of epithelial marker E-cadherin, proved to interact with LDHA, was obviously increased in LDHA-silencing cancer cells. The recruitment of TAMs and the secretion of CCL2 were dramatically reduced after LDHA was knocked down in vitro and in vivo. Taken together, LDHA mediates a vicious cycle of mutual promotion between BCSCs plasticity and TAMs infiltration, which may provide an effective treatment strategy by targeting LDHA for breast cancer patients.

SUBMITTER: Wang S

PROVIDER: S-EPMC8225328 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:LDH-C4 is a lactate dehydrogenase that catalyzes the conversion of pyruvate to lactate. In mammals, ldh-c was originally thought to be expressed only in testis and spermatozoa. Plateau pika (Ochotona curzoniae), which belongs to the genus Ochotona of the Ochotonidea family, is a hypoxia tolerant mammal living 3000-5000 m above sea level on the Qinghai-Tibet Plateau, an environment which is strongly hypoxic. Ldh-c is expressed not only in testis and sperm but also in somatic tissues of plateau pika. In this study, the effects of N-propyl oxamate and N-isopropyl oxamate on LDH isozyme kinetics were compared to screens for a selective inhibitor of LDH-C4. To reveal the role and physiological mechanism of LDH-C4 in skeletal muscle of plateau pika, we investigated the effect of N-isopropyl oxamate on the pika exercise tolerance as well as the physiological mechanism. Our results show that Ki of N-propyl oxamate and N-isopropyl oxamate for LDH-A4, LDH-B4, and LDH-C4 were 0.094 mmol/L and 0.462 mmol/L, 0.119 mmol/L and 0.248 mmol/L, and 0.015 mmol/L and 0.013 mmol/L, respectively. N-isopropyl oxamate is a powerful selective inhibitor of plateau pika LDH-C4. In our exercise tolerance experiment, groups treated with inhibitors had significantly lower swimming times than the uninhibited control group. The inhibition rates of LDH, LD, and ATP were 37.12%, 66.27%, and 32.42%, respectively. Our results suggested that ldh-c is expressed in the skeletal muscle of plateau pika, and at least 32.42% of ATP in the skeletal muscle is catalyzed by LDH-C4 by anaerobic glycolysis. This suggests that pika has reduced dependence on oxygen and enhanced adaptation to hypoxic environment due to increased anaerobic glycolysis by LDH-C4 in skeletal muscle. LDH-C4 in plateau pika plays the crucial role in anaerobic glycolysis and generates ATP rapidly since this is the role of LDH-A4 in most species on plain land, which provide evidence that the native humans and animals in Qinghai-Tibet plateau can adapt to the hypoxia environment.

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Lactate Dehydrogenase-A (LDH-A) Preserves Cancer Stemness and Recruitment of Tumor-Associated Macrophages to Promote Breast Cancer Progression.

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