VHIRtv2011.10.28---Cristina Muñoz Pinedo:針對糖代謝殺死癌細胞

VHIRtv2011.10.28---Cristina Muñoz Pinedo:針對糖代謝殺死癌細胞
Killing cancer cells by targeting glucose metabolism
VHIRtv 於 2011-10-28 上傳

Cristina Muñoz Pinedo. Cell Death Regulation Group IDIBELL (Institut d'Investigació Biomèdica de Bellvitge)

Oncogenic transformation promotes metabolic changes which makes tumors "addicted" to certain metabolites. For this reason, inhibition of tumor metabolism is a promising new therapeutic approach. However, little is known about how metabolic stress triggers tumor cell death.

Glucose depletion has been shown to kill cells either by necrosis (non-apoptotic, pro-inflamatory cell death) or by the mitochondrial pathway of apoptosis. Our studies indicate that several tumor cell lines of different origins die in a non-apoptotic manner when deprived of glucose. However, we have recently described an atypical apoptotic pathway engaged in cells from solid tumors. Surprisingly, apoptosis induced by glucose deprivation is independent of the Bcl-2-regulated mitochondrial pathway. We will describe this apoptotic pathway mediated by caspase-8, which is the initiator caspase engaged by death receptors of the TNF family.

2-deoxyglucose is a non-metabolizable glucose analog which competes with glucose and has shown anti-tumor effects in animals.
Moreover, this compound is been tested in clinical trials. We are currently studying sensitivity of tumor cells, especially sarcoma cell lines, to 2-deoxyglucose. Interestingly, 2-deoxyglucose promoted apoptosis in cell lines in which glucose deprivation promoted necrosis, suggesting different death mechanisms. 2-deoxyglucose activates the mitochondrial apoptotic pathway and regulates several apoptotic proteins in p53-deficient cells. We found death under normoxia to be associated to endoplasmic reticulum stress rather than lack of ATP. We will discuss the signaling pathways involved in responses to nutritional stress and how to improve sensitivity of tumor cells to metabolic targeting.

殺死癌細胞，針對糖代謝
VHIRtv於2011年10月28日上傳

克里斯蒂娜穆尼奧斯 Pinedo。細胞死亡調節組 IDIBELL（研究所D' Investigació Biomèdica Bellvitge）

致癌改造促進代謝的變化，這使得腫瘤“上癮”的某些代謝產物。出於這個原因，抑制腫瘤的代謝，是一種很有前途的新的治療途徑。然而，鮮為人知的是如何代謝應激觸發腫瘤細胞死亡。

已經證明葡萄糖耗盡，殺死細胞壞死（非凋亡，有利於炎性細胞死亡），或細胞凋亡的線粒體途徑。我們的研究表明，不同產地的幾種腫瘤細胞株在非凋亡的方式死亡，當葡萄糖剝奪。然而，我們最近描述了一個不同尋常的從事固體腫瘤細胞的凋亡途徑。令人驚訝的是，缺糖誘導的細胞凋亡Bcl - 2的調節線粒體途徑。我們將描述這 caspase - 8的，這是啟動凋亡從事 TNF家族的死亡受體介導的細胞凋亡途徑。

2 - 脫氧葡萄糖與葡萄糖競爭，並已在動物體內的抗腫瘤作用的非代謝葡萄糖模擬。
此外，這種化合物進行臨床試驗。目前，我們正在研究的腫瘤細胞，尤其是肉瘤細胞株的敏感性，2 - 脫氧葡萄糖。有趣的是，2 - 脫氧葡萄糖促進糖剝奪促進壞死細胞凋亡，提示不同的死亡機制。 2 - 脫氧葡萄糖激活線粒體凋亡通路和調節 p53缺失的細胞凋亡的蛋白質。我們發現在低氧死亡的關聯，而不是缺乏ATP的內質網應激。我們將討論涉及營養應激反應，以及如何提高腫瘤細胞的代謝針對靈敏度的信號通路。