Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Nat Commun. 2020 Apr 20;11(1):1869. doi: 10.1038/s41467-020-15795-8.
Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.
有证据表明，禁食在各种癌症中都能发挥广泛的抗肿瘤作用，包括结直肠癌（CRC）。然而，这种反应的机制尚不清楚。我们研究了禁食对 CRC 中葡萄糖代谢和恶性肿瘤的影响。我们发现，禁食在抑制 CRC 细胞有氧糖酵解和增殖的过程中，上调了胆固醇生成基因法呢基二磷酸法呢基转移酶 1（FDFT1）的表达。此外，FDFT1 的下调与 CRC 中的恶性进展和不良预后相关。此外，FDFT1 作为 CRC 中的关键肿瘤抑制因子发挥作用。在机制上，FDFT1 通过负调控 AKT/mTOR/HIF1α 信号通路来发挥其肿瘤抑制功能。此外，mTOR 抑制剂可以与禁食协同抑制 CRC 的增殖。这些结果表明，FDFT1 是禁食反应的关键下游靶标，可能参与 CRC 细胞的葡萄糖代谢。我们的研究结果提示在 CRC 治疗中的应用，以及胆固醇生成基因和糖酵解之间的潜在相互作用。
