CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in-vivo and in-vitro models

CD147 (Basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDAC). CD147 expression has been associated to poor prognosis in many malignancies. To clarify the role of CD147 in pancreatic cancer we silenced CD147 in PDAC cells. Interestingly, CD147 RNAi significantly reduced the cell proliferation rate. CD147 is required for expression and function of monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4) which are the natural transporters of lactate. Excessive lactate production is an early hallmark of cancer known as the Warburg-effect. A high rate of lactate production was demonstrated in PDAC cells also in-vitro suggesting that they maintain the characteristic glycolytic phenotype in culture. We performed RT-PCR and immunohistology to demonstrate MCT1 and MCT4 mRNA and protein expression in human PDAC cells and tumor samples. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 protein level. Importantly, CD147 silencing inhibited the expression and function of MCT1 and MCT4 which resulted in an increase in intracellular lactate concentration. Addition of exogenous lactate inhibited cancer-cell growth in a dose dependent fashion. In-vivo, inducible short hairpin RNA (shRNA) mediated CD147 silencing in MiaPaCa2 cells reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM-assay) and inhibited tumorigenicity in a xenograft model in nude-mice. Our results demonstrate that CD147 confers a significant growth advantage for PDAC cells by a mechanism that involves the function of CD147 as an ancillary protein of lactate transporter heteromers. In addition these findings support the idea that in PDAC the Warburg-effect is mandatory to sustain the high proliferation rate of cancer cells. Moreover, they indicate that inhibiting the lactate transporters represents a potential therapeutic strategy for PDAC.