過度攝取加工糖類及碳水化合物的高糖飲食方式近年來已成為現代人的飲食習慣，並且增加罹患代謝性相關疾病及癌症等機率。而我們實驗室也發現負責調控糖質新生的速率限制酵素-磷酸烯醇丙酮酸羧化激酶 (phosphoenolpyruvate carboxykinase, pepck) 在果蠅高糖飲食誘導的腫瘤進程中會促進腫瘤細胞生長，而磷酸烯醇丙酮酸羧化激酶有兩種亞型，一種是位於細胞質的PEPCK-C (PEPCK1)；另一種是位於粒線體的PEPCK-M (PEPCK2)。然而，磷酸烯醇丙酮酸羧化激酶 1和2如何促進時間及空間上 HDS 誘導的腫瘤進展的分子機制仍不清楚。在這裡，使用果蠅 Ras/Src 腫瘤模型，我們發現降低腫瘤細胞中的磷酸烯醇丙酮酸羧化激酶1 或 2不僅減少了 HDS 誘導的腫瘤生長/負擔也使Wingless/Wnt及TOR-pS6訊號下降，並且通過部分地下調 dTOR、d4EBP 或 drpS6基因表達量。令人驚訝的是，各別降低磷酸烯醇丙酮酸羧化激酶1或2基因表達後恢復原先因高糖誘導腫瘤生長而破壞的果蠅眼睛發育指標-第二有絲分裂波，透過TOR-pS6訊號時間及空間上的活化。最後，我們使用硫酸肼 (Hydrazinium sulfate, HS)作為磷酸烯醇丙酮酸羧化激酶的抑制劑，可減少 HDS 誘導的發育延遲和腫瘤動物對 pepck1 敲低的荷瘤動物的致死率。綜合以上所述，這些證據說明通過磷酸烯醇丙酮酸羧化激酶1和2上調Wingless及TOR訊號傳遞而促進高糖飲食誘導的腫瘤進展，造成發育遲緩及致死。我們的研究提供由基礎分子、細胞和生物個體層次解釋高糖飲食誘導的腫瘤進展依賴於磷酸烯醇丙酮酸羧化激酶1和2的上調及強調磷酸烯醇丙酮酸羧化激酶軸作為高糖飲食誘導的代謝紊亂相關的癌症的治療目標及方式。

High dietary sugar (HDS) is a modern dietary practice with excessive consumption of carbohydrates including added sugars, increases the risk of metabolic disorders and their associated cancers. Our unpublished data have shown that cytosolic phosphoenolpyruvate carboxykinase1 (PEPCK1) and mitochondrial PEPCK2, key rate-limiting enzymes in gluconeogenesis, are upregulated to promote HDS-induced Ras/Src tumor growth in Drosophila. However, the molecular mechanisms by which PEPCK1 and PEPCK2 tempo-spatially promote HDS-induced tumor progression remain unclear. Here, using Drosophila Ras/Src tumor model, we found that pepck1 or pepck2 knockdown in tumor cells not only reduces HDS-induced tumor growth/burden but also decreases Wingless/Wnt and TOR-pS6 signaling partly via downregulation of dTOR, d4EBP, and drpS6. Surprisingly, pepck1 or pepck2 knockdown restores tempo-spatial activation of TOR-pS6 signaling in the second mitotic wave (SMW) for eye development, which is abolished in Ras/Src tumor bearing animals fed HDS. Finally, we found that Hydrazinium sulfate (HS), a PEPCK inhibitor, reduces HDS-induced developmental delay and tumor bearing animal lethality in tumor bearing animals with pepck1 knockdown. Taken together, these results suggest a novel mechanism by which PEPCK1 and PEPCK2 promote HDS-aggravated tumor progression to cause developmental delay and lethality by upregulating Wingless/Wnt and TOR-pS6 signaling. Our research explains the molecular, cellular, and organismal basis of HDS-aggravated tumor progression to be dependent on upregulation of PEPCK1 and PEPCK2, moreover; highlights the PEPCK axis as a therapeutic target for cancers associated with HDS-induced metabolic disorders.

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