腫瘤細胞於能量代謝上最大的特點就是不論含氧量是否充足，腫瘤細胞都優先利用 glycolysis來降解葡萄糖以產生ATP此即所謂的Warburg effect °因此針對改變腫瘤能 量代謝機轉成為抗癌的策略之一。在我們執行計晝的過程中我們發現具有抑制脂肪生 成作用（adipogenesis)且能誘發腫瘤細胞凋亡(apoptosis)的藥物如aspirin與vitexin皆 能抑制脂肪細胞glycolysis的速率限制酵素Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)表現。進一步先期實驗亦發現vitexin能抑制口腔腫瘤細胞的 GAPDH表現。另外，此兩種藥物皆藉由tumor suppressor p53訊息傳導路徑來調控 腫瘤細胞凋亡與抑制脂肪細胞的脂肪生成作用。前述結果已發表於SCI期刊或審稿 中。依據已獲之結果我們可預期glycolysis、apoptosis與adipogenesis三者間存在著 某種相互依存與調控的關係，且p53於此一調控機制中也扮演著相當關鍵的角色。然 而針對此一議題的研究與成果相對的闕如，因此激發我們對-「1.抗癌藥物如何改變腫 瘤細胞的能量代謝、2.改變能量代謝路徑與細胞凋亡、脂肪生成三者間的相互關係」-相關議題的興趣，故擬申請二年期計晝進行深入的探討。 本計晝我們規劃為二年期計晝，其目的乃在探討細胞能量代謝與脂肪生成、細胞凋亡 之相互作用，特別是對腫瘤細胞之影響。對於本計晝我們的規劃簡述如下：（1).第一年 期：抗癌藥物於腫瘤細胞能量代謝之探討。我們擬以aspirin與vitexin處理口腔癌細 胞後檢測其對能量代謝路徑之影響與改變。第二年期：第二年之主要任務乃在探討 glycolysis、apoptosis、adipogenesis三者間相互調控的關係。依據我們先前的實驗結 果我們假設抑制糖解作用後能量代謝路徑會以pentose phosphate pathway為優先，此 一轉變導致細胞對能量代謝的改變進而誘發細胞凋亡或抑制脂肪生成。然而，關鍵的 轉捩點為何？?調控機制為何？？此外，我們也將探討p53於此一機制中所扮演之角色。 Metabolism in tumors deviates significantly from that of normal tissues. Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. Cancer cells adjust their metabolic profile to optimize continuous cell growth and proliferation while situated in an abnormal and sometimes hostile environment. This so-called ‘metabolic transformation’ phenomenon is crucial for their survival and for disease progression. Therefore, identifying key metabolic alterations in cancer may provide new therapeutic strategies to specifically target malignant cells. We found that drugs involved in adipogenesis and apoptosis such as aspirin and vitexin diminished the expression of rate-limiting enzyme of glycolysis, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, adipogenesis and apoptosis regulated by tumor suppressor p53. It implicated that there are some relationships about regulation among glycolysis, apoptosis and adipogenesis. Tumor suppressor p53 may play a key role in this regulation. We plan to carry out this study at two stages, (1) study on how the anti-tumor drugs changes the metabolism. We can understand several major signal pathways that cause cell metabolism changed. (2) Based on the result of the first stage, we will concentrate our attention on the relationship among glycolysis, apoptosis and adipogenesis. We postulate that inhibited glycolysis leads to use pentose phosphate pathway (PPP) preferentially to generation of ATP. Therefore, drive cells to induce apoptosis or inhibit adipogenesis. We have assigned the coordinator of this study, who had the master degree of National Chung Shing University at 1989, PhD. candidate of Chung Shan Medical University and serving as a technician for many years in our laboratory. We expect that we can investigate several major signal mechanisms of glycolysis deepen and intact during the following two years, in order to offer the theory foundation that the glycolysis uses and clinical application.
