Salvioli S, Storci G, Pinti M, Quaglino D, Moretti L, Merlo-Pich M, Lenaz G, Filosa S, Fico A, Bonafè M, Monti D, Troiano L, Nasi M, Cossarizza A, Franceschi C
Department of Experimental Pathology, University of Bologna, Bologna, Italy.
Cell Death Differ. 2003 Feb;10(2):163-74. doi: 10.1038/sj.cdd.4401124.
The onset of resistance to drug-induced apoptosis of tumour cells is a major problem in cancer therapy. We studied a drug-selected clone of promyelocytic HL-60 cells, called HCW-2, which display a complex resistance to a wide variety of apoptosis-inducing agents and we found that these cells show a dramatic increase in the expression of heat shock proteins (Hsps) 70 and 27, while the parental cell line does not. It is known that stress proteins such as Hsps can confer resistance to a variety of damaging agents other than heat shock, such as TNF-alpha, monocyte-induced cytotoxicity, and also play a role in resistance to chemotherapy. This elevated expression of Hsps is paralleled by an increased activity of mitochondrial metabolism and pentose phosphate pathway, this latter leading to high levels of glucose-6-phosphate dehydrogenase and, consequently, of glutathione. Thus, the apoptotic-deficient phenotype is likely because of the presence of high levels of stress response proteins and GSH, which may confer resistance to apoptotic agents, including chemotherapy drugs. Moreover, the fact that in HCW-2 cells Hsp70 are mainly localised in mitochondria may account for the increased performances of mitochondrial metabolism. These observations could have some implications for the therapy of cancer, and for the design of combined strategies that act on antioxidant defences of the neoplastic cell.
肿瘤细胞对药物诱导凋亡产生抗性是癌症治疗中的一个主要问题。我们研究了一种经药物筛选的早幼粒细胞HL-60细胞克隆，称为HCW-2，它对多种凋亡诱导剂表现出复杂的抗性，并且我们发现这些细胞中热休克蛋白（Hsps）70和27的表达显著增加，而亲代细胞系则没有。已知诸如Hsps等应激蛋白可赋予细胞对除热休克以外的多种损伤剂的抗性，如肿瘤坏死因子-α、单核细胞诱导的细胞毒性，并且在对化疗的抗性中也起作用。Hsps的这种表达升高与线粒体代谢和磷酸戊糖途径活性的增加同时出现，后者导致葡萄糖-6-磷酸脱氢酶水平升高，进而导致谷胱甘肽水平升高。因此，凋亡缺陷表型可能是由于高水平的应激反应蛋白和谷胱甘肽的存在，它们可能赋予细胞对包括化疗药物在内的凋亡剂的抗性。此外，在HCW-2细胞中Hsp70主要定位于线粒体这一事实可能解释了线粒体代谢性能的提高。这些观察结果可能对癌症治疗以及作用于肿瘤细胞抗氧化防御的联合策略的设计具有一些启示。
