Abstract
Excess lactate production due to enhanced aerobic glycolysis is characteristic of malignant cancers, which is also intimately associated with poor cancer prognoses. Although tumor-associated lactate contributes to all major steps in carcinogenesis, its action mechanism remains obscure. To understand the molecular mechanism of the lactate-induced tumor metastatic process, we identified an array of lactate-responsive genes via transcriptome analysis of a metformin-induced hyper-glycolytic liver cancer model. Gene set enrichment analysis suggested E2F-RB pathway as the dominant regulator of the lactate-induced gene expression. We experimentally verified that lactate indeed activates E2F-mediated transcription by promoting E2F1 protein accumulation through a posttranscriptional mechanism. Literature-based analysis of target pathways potentially modulated by 136 top-ranked genes indicated that genes functioning in cell-cell or cell-matrix communications dominate the lactate-induced gene expression. Especially, those regulating microtubule functions, including a group of kinesin family members, were significantly up-regulated in lactate- and E2F1-dependent manners. Depletion of E2F1 or kinesins (KIF2C, KIF18B, KIF20A) led to deformation of microtubule structures, impairing cell motility as much as the deficit in lactate production. These results indicate that E2F pathway activation by tumor-associated lactate and subsequent transcriptional activation of microtubule functions play crucial roles in tumor metastasis, providing mechanistic clues to cell motility-directed anti-cancer strategies.
Highlights
The pathophysiological conditions of tumor microenvironment are closely connected to various stages of tumor development as well as the response to cancer therapeutic approaches
Univariate analysis indicated that higher E2F1 activity is significantly associated with (Figure S4E). These results indicate that E2F activity is closely associated with the activity of advanced tumor stages (p < 0.01) (Table S2). These results indicate that E2F1 may play a significant role microtubule polymerization or assembly process, and suggest that lactate-induced E2F1 activation in the prognosis of HCC patients by regulating tumor metastatic processes as well as tumor growth
In this study we showed that among the 5 kinesin members whose transcription is up-regulated in a lactate-dependent manner, depletion of KIF2C, KIF18B and KIF20A results in deregulation of microtubule structure as well as impairment of cell motility, providing experimental supports for the notion that lactate promotes cell motility by regulating microtubule functions through the induction of microtubule modulating genes such as kinesins
Summary
The pathophysiological conditions of tumor microenvironment are closely connected to various stages of tumor development as well as the response to cancer therapeutic approaches. Cancers 2019, 11, 274 metabolite present in abundance within tumor microenvironment [3,4]. Increased glycolytic flux associated with malignant tumor cells leads to enhanced lactate production even in the presence of oxygen. This phenomenon, termed “aerobic glycolysis” or “Warburg effect”, is a critical part of the deregulated cellular energetics in cancers cells, which has been recognized as the hallmark of cancer recently [5,6]. The lactate-enriched microenvironment has been regarded as the potential driver of tumor growth and metastasis and as a favorable target for cancer therapy
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