The glycolytic enzyme pyruvate kinase M2 (PKM2) exists in both catalytically inactive dimeric and active tetrameric forms. In cancer cells, PKM2 dimer predominance contributes to tumor growth by triggering glycolytic reprogramming. However, the mechanism that promotes PKM2 dimer predominance over tetramer in cancer cells remains elusive. Here, we show that pulsatile phosphofructokinase (PFK-1) activity results in PKM2 dimer predominance. Mathematical simulations predict that pulsatile PFK-1 activity prevents the formation of PKM2 tetramer even under high levels of fructose-1,6-bisphosphate (FBP), a PKM2 tetramer-promoting metabolite produced by PFK-1. We experimentally confirm these predictions at the single-molecule level by providing evidence for pulsatile PFK-1 activity-induced synchronized dissociation of PKM2 tetramers and the subsequent accumulation of PKM2 dimers under high levels of FBP in HeLa cells. Moreover, we show that pulsatile PFK-1 activity-induced PKM2 dimer predominance also controls cell proliferation. Thus, our study reveals the significance of pulsatile PFK-1 activity in cancer cell metabolism.

中文翻译：

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癌细胞中的糖酵解重编程：脉动 PFK-1 活性诱导 PKM2 二聚体优势。


糖酵解酶丙酮酸激酶 M2 (PKM2) 以无催化活性的二聚体和活性四聚体形式存在。在癌细胞中，PKM2 二聚体优势通过触发糖酵解重编程促进肿瘤生长。然而，在癌细胞中促进 PKM2 二聚体优于四聚体的机制仍然难以捉摸。在这里，我们发现脉冲式磷酸果糖激酶 (PFK-1) 活性导致 PKM2 二聚体占优势。数学模拟预测，即使在高水平的果糖 1,6-二磷酸 (FBP)（一种由 PFK-1 产生的 PKM2 四聚体促进代谢物）下，脉冲 PFK-1 活性也会阻止 PKM2 四聚体的形成。我们通过实验在单分子水平上证实了这些预测，为 HeLa 细胞中脉冲 PFK-1 活性诱导的 PKM2 四聚体同步解离以及随后在高水平 FBP 下 PKM2 二聚体的积累提供了证据。此外，我们发现脉冲 PFK-1 活性诱导的 PKM2 二聚体优势也控制细胞增殖。因此，我们的研究揭示了脉冲 PFK-1 活性在癌细胞代谢中的重要性。