Salloum Darin, Mukhopadhyay Suman, Tung Kaity, Polonetskaya Aleksandra, Foster David A
Corresponding Author: David A. Foster, Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10065.
Mol Cancer Ther. 2014 Mar;13(3):733-41. doi: 10.1158/1535-7163.MCT-13-0762. Epub 2014 Jan 16.
The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids, and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin-indicating that the enhanced need for serum lipids creates a synthetic lethal phenotype that could be exploited therapeutically. Although depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible. Suppressing macropinocytosis in Ras-driven cancer cells also created sensitivity to suppression of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). It is speculated that this property displayed by Ras-driven cancer cells represents an Achilles' heel for the large number of human cancers that are driven by activating Ras mutations.
正常细胞向癌细胞的转变涉及从分解代谢到合成代谢的转变，包括葡萄糖摄取增加以及糖酵解中间产物转向细胞生长所需的核苷酸、氨基酸和脂质。营养物质摄取中一个未得到充分重视的方面是血清脂质的利用。我们研究了人类癌细胞对血清脂质的依赖性，并在此报告，Ras驱动的人类癌细胞在增殖和存活方面都独特地依赖血清脂质。去除血清脂质也会使Ras驱动的癌细胞对雷帕霉素敏感，这表明对血清脂质的需求增加产生了一种合成致死表型，可用于治疗。虽然剥夺人类的血清脂质不切实际，但抑制脂质摄取是可能的。抑制Ras驱动的癌细胞中的巨胞饮作用也会使其对抑制哺乳动物/雷帕霉素复合物1（mTORC1）的机制靶点敏感。据推测，Ras驱动的癌细胞所表现出的这种特性是由激活Ras突变驱动的大量人类癌症的致命弱点。
