In the current study, we determined the critical roles of c-Myc–LDHA axis in aerobic glycolysis and its cellular functions in pancreatic cancer. First, we observed that c-Myc and LDHA are concomitantly up-regulated in pancreatic cancer specimens and cell lines, and up-regulated c-Myc expression and LDHA expression lead to poor prognosis in pancreatic cancer patient. Second, suppression of c-Myc resulted in decreased expression of LDHA, reduced aerobic glycolysis, growth arrest and inability of invasion; meanwhile, knockdown of LDHA mimicked this effect. Third, inhibition of aerobic glycolysis abolished the effects of c-Myc–LDHA axis on cell growth and metastasis in vitro. Therefore, our findings demonstrated that c-Myc–LDHA axis contributed to the Warburg effect, thus facilitating tumor development and progression in pancreatic cancer.
Metabolic alternations in cancers not only support energy requirements but also provide enormous biosynthetic needs [
17]. c-Myc contributes to the glucose metabolic reprogramming of tumor cells through several different targets [
6]. Briefly, through up-regulation of glucose transporters, c-Myc increases the uptake of glucose; by regulation of LDHA and the lactate transporter MCT1, c-Myc promotes the Warburg effect; c-Myc also prevents pyruvate to enter the TCA cycle by regulating pyruvate dehydrogenase (PDK) expression [
15]. Consistent with this, c-Myc regulates LDHA expression in pancreatic cancer and suppression of c-Myc significantly inhibited the Warburg effect. In pancreatic cancer, it has been demonstrated that the expression level of LDHA is up-regulated in both clinical specimens and cell lines, and forced expression of LDHA promoted tumor growth and tumorigenicity of pancreatic cancer [
18]. Overexpressed LDHA promotes the production of lactate and further contributes to the acidification of tumor microenvironment [
19]. A low pH induced by extracellular acidification favors the activation of proteases, including MMPs [
20] and urokinase-type plasminogen activator [
21], which ultimately result in extracellular matrix degradation and facilitate cancer cells to metastasis [
22]. In our study, we found both c-Myc expression and LDHA expression are closely associated with tumor size and TNM stage and indicate poor prognosis in patients with pancreatic cancer. Meanwhile, inhibition of c-Myc–LDHA axis inhibits glucose utilization, lactate production, cell proliferation, migration and invasion. All these can be explained by the favorable tumor microenvironment induced by c-Myc–LDHA axis facilitates tumor progression. However, because c-Myc regulates the expression of multiple targeted genes, it is hard to draw a conclusion that this cell phenotype was mediated by LDHA. And because LDHA expression is also regulated by many other transcription factors including HIF1a [
23] and KLF4 [
12] in pancreatic cancer, the oncogenic activity of LDHA in Warburg effect and tumor progression also remains to be further analyzed. Despite the presence of these limits, we at least confirmed the oncogenic roles of c-Myc–LDHA axis on tumor progression through enhancing Warburg effect.
In conclusion, our study provided both clinical and mechanistic evidences supporting that c-Myc modulates LDHA expression and that the c-Myc–LDHA axis exhibits a critical role in aerobic glycolysis and tumor progression in pancreatic cancer. Our research identified dysregulated c-Myc–LDHA axis as a promising new molecular target for the design of novel therapeutic to control development and progression of pancreatic cancer.