Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression

Abstract

Background Pancreatic adenocarcinoma (PAAD) a highly lethal malignancy. The current use of clinical parameters may not accurately predict the clinical outcome, which further renders the unsatisfactory therapeutic outcome. Methods In this study, we retrospectively analyzed the clinical‐pathological characteristics and prognosis of 253 PAAD patients. Univariate, multivariate, and Kaplan‐Meier survival analyses were conducted to assess risk factors and clinical outcomes. For functional study, we performed bidirectional genetic manipulation of lactate dehydrogenase A (LDHA) in PAAD cell lines to measure PAAD progression by both in vitro and in vivo assays. Results LDHA is particularly overexpressed in PAAD tissues and elevated serum LDHA‐transcribed isoenzymes‐5 (LDH‐5) was associated with poorer patients’ clinical outcomes. Genetic overexpression of LDHA promoted the proliferation and invasion in vitro, and tumor growth and metastasis in vivo in murine PAAD orthotopic models, while knockdown of LDHA exhibited opposite effects. LDHA‐induced L‐lactate production was responsible for the LDHA‐facilitated PAAD progression. Mechanistically, LDHA overexpression reduced the phosphorylation of metabolic regulator AMPK and promoted the downstream mTOR phosphorylation in PAAD cells. Inhibition of mTOR repressed the LDHA‐induced proliferation and invasion. A natural product berberine was selected as functional inhibitor of LDHA, which reduced activity and expression of the protein in PAAD cells. Berberine inhibited PAAD cells proliferation and invasion in vitro, and suppressed tumor progression in vivo. The restoration of LDHA attenuated the suppressive effect of berberine on PAAD. Conclusions Our findings suggest that LDHA may be a novel biomarker and potential therapeutic target of human PAAD.

Identification of Clinical and Tumor Microenvironment Characteristics of Hypoxia-Related Risk Signature in Lung Adenocarcinoma

“…The hypoxia-related risk signature consists of eight hypoxia-related genes, including LDHA, DCN, PGK1, PFKP, FBP1, LOX, ENO3, and CXCR4. LDHA is an enzyme that catalyzes the mutual conversion of pyruvate and lactic acid, as well as promotes invasion, metastasis, nest loss, and apoptosis resistance in various cancers ( Cheng et al, 2021 ; Crowley et al, 2021 ; Gupta et al, 2021 ). Multiple studies have suggested that DCN can suppress lung cancer progression by blocking receptor tyrosine kinases ( Horvath et al, 2014 ).…”

Single-Cell Transcriptome Reveals the Metabolic and Clinical Features of a Highly Malignant Cell Subpopulation in Pancreatic Ductal Adenocarcinoma

“…Alphaenolase (EN O 1), one of the three enolase isozymes, participates in the adhesion, invasion, and metastasis of PDAC by controlling integrin expression (Principe et al, 2017). Lactate dehydrogenase A (LDHA) is a cytoplasmic enzyme, and overexpression of LDHA promotes PDAC proliferation and invasion in vitro by regulating phosphorylation of AMPK and mTOR (Cheng et al, 2021). Inhibition of LDHA has no significant toxic effects on normal tissues; therefore, LDHA may serve as a promising target for tumor therapy.…”

Cellular metabolism in pancreatic cancer as a tool for prognosis and treatment (Review)

“…Additionally, phosphorylation on Ser226 in GLUT1 was identified as a key event for the enhanced cell surface localization of GLUT1 and for the regulation of glucose transport (55). A sustained elevated glycolytic flux in PDAC is markedly connected with an increased expression of rate-limiting glycolytic enzymes like phosphofructokinase 1 and lactate dehydrogenase A (LDHA) (56)(57)(58), and there is also evidence of glycolytic enzymes regulating the epithelial-mesenchymal transition (EMT) in PC cells, inducing PC cell invasion and metastasis as well as promoting tumor angiogenesis (59)(60)(61)(62)(63). The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway activated by oncogenic KRAS together with hypoxic conditions known to be present in PDAC increase glucose uptake and the expression of glycolytic enzymes, which then leads to the establishment of an acidic microenvironment and the promotion of tumorigenesis (57,64).…”