Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.

中文翻译：

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PFKFB2调节胰腺癌细胞中的糖酵解和增殖。

肿瘤细胞通过糖酵解和戊糖磷酸途径增加葡萄糖代谢，以满足快速细胞增殖的生物能和生物合成需求。6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶家族（PFKFB1-4）通过合成果糖-2,6-双磷酸果糖（F2,6BP）是葡萄糖代谢的关键调节剂，而果糖-2,6-二磷酸果糖是一种有效的激活剂。糖酵解。先前的研究报道了PFKFB同工酶以及特定PFKFB同工酶的mRNA剪接变体的共表达，表明其具有非冗余功能。多数证据表明对PFKFB活性需要增加肿瘤细胞的糖酵解和致癌性，这来自对PFKFB3和PFKFB4同工酶的研究。在这项研究中，我们显示PFKFB2同工酶在各种来源的肿瘤细胞系中表达，相对于正常胰腺组织而言，过表达并位于胰腺腺癌的核中。然后，我们证明了两个PFKFB2 mRNA剪接变体在细胞内的定位差异，并且当异位表达时，胞质定位的mRNA剪接变体导致F2,6BP的更大增加，这与葡萄糖摄取的增加相吻合，与定位于核。然后，我们表明PFKFB2表达是稳态F2,6BP水平，糖酵解活性和胰腺腺癌细胞增殖所必需的。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。相对于正常的胰腺组织。然后，我们证明了两个PFKFB2 mRNA剪接变体在细胞内的定位差异，并且当异位表达时，胞质定位的mRNA剪接变体导致F2,6BP的更大增加，这与葡萄糖摄取的增加相吻合，与定位于核。然后，我们表明PFKFB2表达是稳态F2,6BP水平，糖酵解活性和胰腺腺癌细胞增殖所必需的。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。相对于正常的胰腺组织。然后，我们证明了两种PFKFB2 mRNA剪接变体在细胞内的定位差异，并且当异位表达时，胞质定位的mRNA剪接变体导致F2,6BP的更大增加，这与葡萄糖摄取的增加相吻合，与定位于核。然后，我们表明PFKFB2表达是稳态F2,6BP水平，糖酵解活性和胰腺腺癌细胞增殖所必需的。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。当异位表达时，与定位于细胞核的mRNA剪接变体相比，胞浆定位的mRNA剪接变体引起F2，6BP的更大增加，这与葡萄糖摄取的增加同时发生。然后，我们表明PFKFB2表达是稳态F2,6BP水平，糖酵解活性和胰腺腺癌细胞增殖所必需的。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。当异位表达时，与定位于细胞核的mRNA剪接变体相比，胞浆定位的mRNA剪接变体引起F2，6BP的更大增加，这与葡萄糖摄取的增加同时发生。然后，我们表明PFKFB2表达是稳态F2,6BP水平，糖酵解活性和胰腺腺癌细胞增殖所必需的。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。糖酵解活性和胰腺腺癌细胞的增殖。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。糖酵解活性和胰腺腺癌细胞的增殖。总之，本研究可为详细研究PFKFB2对胰腺腺癌细胞的糖酵解和致癌表型的需求提供依据。