Abstract 1186: Regulatory role of lactate dehydrogenase A during head and neck carcinogenesis

Abstract

Background: Head and Neck (H&N) cancer is one of the most prevalent neoplasms worldwide. It is well accepted that H&N cancer development is a multistep process resulting from internal and external cellular/molecular and physiological challenges leading to a number of genetic, epigenetic and metabolic abnormalities. In comparison with mitochondrial energy production in normal cells, previous studies have shown that cancer cells preferentially utilize the by-products of glycolysis, regardless of oxygen status, as an energy source. In view of this physiological variance, many investigations demonstrated that manipulations of glycolytic enzymes could potentially modulate cell malignancy of various cancers. Lactate dehydrogenase A (LDHA), one of the glycolytic enzymes essential for conversion of pyruvate into lactate, has been previously emphasized for its potential cancer-promoting effect; nevertheless, LDHA-mediated regulation for cellular malignancy and its underlying molecular mechanisms during H&N carcinogenesis is still poorly understood. Methods: Current experimental scheme was two-folds. It was initiated by histological analysis for LDHA expression in normal and tumorous tongue epithelium from animals treated with oral carcinogen 4-Nitroquinoline 1-oxide (4-NQO) to define potential role of LDHA between normal and cancerous oral tissues. Further in vitro establishment of genetic (shRNA) and chemical (oxamate) induced LDHA deficient H&N cancer cells were carried out and multifaceted cancer phenotypes including cell growth/survival, cell motility, cell differentiation and sensitivity to chemotherapeutic drug cisplatin were examined in LDHA deficient cells. Results: 4-NQO treatment stimulated tongue epithelial hyperplasia as histological analysis showed progressive dysplasia/carcinoma correlated with longer (12-week) 4-NQO treatment. LDHA expression was detected in basal layer of normal mouse tongue epithelium and enriched in suprabasal layer in 4-NQO induced hyperplastic/dysplastic tongue precancerous epithelium as well as aggressive tongue carcinoma suggesting that LDHA plays an important role during tongue carcinogenesis. In agreement with in vivo data, LDHA is highly expressed in H&N cancer cells from different origins (tongue, oropharyngeal or oral squamous cells). LDHA deficient head and neck H&N cancer cells were successfully established and showed (1) decreased cell growth; (2) downregulated cell migration, invasion and anchorage-independent growth; (3) greater expression of differentiation marker involucrin and (4) increased cisplatin sensitivity in comparison with control cells revealing LDHA-mediated tumorigenic regulations. Conclusions: Present study confirmed that suppression of glycolytic enzymes LDHA could downregulate cell malignancy in H&N cancer cells. The outcomes are of great potential to develop the metabolism mediated anti-cancer treatment for H&N cancer patients.

Citation Format: Tsai-Ying Chen, Wan-Jung Chang, Chang-Yi Chen, Wan-Chun Li. Regulatory role of lactate dehydrogenase A during head and neck carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1186. doi:10.1158/1538-7445.AM2015-1186