Abstract
Lactate dehydrogenase A (LDHA) has been reported to be involved in the initiation and progression of tumors. However, the potential role of LDHA in pituitary adenoma (PA) remains unknown. In this study, we showed that the expression levels of LDHA mRNA and protein were significantly elevated in invasive PA samples, and positively correlated with higher Ki-67 index. Overexpression of LDHA in a PA cell line (GH3) promoted glucose uptake through the upregulation of glucose transporter-1 (Glut1), lactate secretion and induced cellular invasion by upregulation of matrix metalloproteinase2 (MMP2). LDHA also promoted GH3 cell proliferation through induction of cell cycle progression via activation of the Akt-GSK-3β-cyclinD1 pathway. Accordingly, oxamate-induced inhibition of LDHA suppressed glucose uptake, lactate secretion, invasion and proliferation in GH3 cells via down regulation of Glut1 and MMP2 expression and inhibition of the Akt-GSK-3β-cyclinD1 pathway. Moreover, oxamate induced GH3 cell apoptosis by increasing mitochondrial reactive oxygen species (ROS) generation. In vivo, LDHA overexpression promoted tumor growth, and oxamate delayed tumor growth. In primary PA cell cultures, oxamate also effectively suppressed invasion and proliferation. Our data indicate that LDHA is involved in promoting the progression of PA, and oxamate might be a promising therapeutic agent for the treatment of PA.
Highlights
Human pituitary adenomas (PA) are generally considered benign tumors that account for 10–15% of primary intracranial neoplasms[1]
These results suggested that Lactate dehydrogenase A (LDHA) may be an important regulator of the invasion and proliferation of PA cells
We demonstrated that elevated LDHA was correlated with the invasiveness and proliferation of human PA samples and confirmed that overexpression of LDHA promoted PA cell invasion and proliferation both in vitro and in vivo
Summary
Human pituitary adenomas (PA) are generally considered benign tumors that account for 10–15% of primary intracranial neoplasms[1]. Despite their histologically benign nature, a subset of PA can invade the surrounding tissues, including the dura, bones, and sinuses. Clarification of the factors responsible for the aggressive behavior of PA is crucial for developing novel treatment strategies and evaluating prognosis in patients with PA. Invasive PA is regarded as an intermediate stage in tumor development toward carcinoma[10] Despite their histologically benign status, invasive PA have a tendency toward malignant biological behavior. Our findings support the use of novel therapeutic strategies for patients with PA, those with invasive PA
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