Abstract
The mevalonate pathway is known for the synthesis of cholesterol, but recent studies have reported that it also controls Hippo signaling, which is critical for the regulation of organ size and tumorigenesis. Here, we discover that the suppression of the mevalonate pathway inhibits the growth and proliferation of colon cancer cell lines. The results of transcriptomic and proteomic assays suggested that the mevalonate pathway controls multiple signaling pathways relevant to cell proliferation, and the results were further confirmed using western blot, PCR, and immunofluorescence assays. As cell proliferation is an energy-consuming process, we postulate that the mevalonate pathway may also control nutrient uptake to coordinate the processes of energy supply and cell proliferation. Here, we found that lovastatin, a mevalonate pathway inhibitor, suppresses glucose and amino acid uptake and lactate acid production. More importantly, mevalonic acid itself is sufficient to promote glucose uptake by colon cancer cells. In addition, we found that colon cancer tissues displayed a higher expression of mevalonate pathway enzymes, which may promote cell growth and stimulate energy uptake. Together, our findings establish the mevalonate pathway as a critical regulator in coordinating energy input and cell proliferation.
Highlights
Cell proliferation and growth are under the tight control of intracellular signaling pathways and the extracellular environment, such as energy availability
Wnt and YAP/TAZ are two signaling pathways that control cell growth and proliferation. Given their key roles in the pathogenesis of colon cancer, we used colon cancer cell lines to test the effect of lovastatin on cell proliferation
The results show that proliferation was significantly suppressed by lovastatin treatment in all cell lines tested, except for HT-29 (Fig. 1a and S-Fig. 1A–D)
Summary
Cell proliferation and growth are under the tight control of intracellular signaling pathways and the extracellular environment, such as energy availability. Wnt and YAP/TAZ are two signaling pathways that control cell growth and proliferation. The results showed that lovastatin treatment significantly downregulated RNA and protein expression in RKO and SW480 cells, and the addition of exogenous MVA recovered the expression (Fig.1e, f and S-Fig. 2B).
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