Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression

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.