title: Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism.
abstract: 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.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. ssalviol@alma.unibo.it
authors.forename: S
authors.initials: S
authors.lastname: Salvioli
authors.forename: G
authors.initials: G
authors.lastname: Storci
authors.forename: M
authors.initials: M
authors.lastname: Pinti
authors.forename: D
authors.initials: D
authors.lastname: Quaglino
authors.forename: L
authors.initials: L
authors.lastname: Moretti
authors.forename: M
authors.initials: M
authors.lastname: Merlo-Pich
authors.forename: G
authors.initials: G
authors.lastname: Lenaz
authors.forename: S
authors.initials: S
authors.lastname: Filosa
authors.forename: A
authors.initials: A
authors.lastname: Fico
authors.forename: M
authors.initials: M
authors.lastname: Bonafè
authors.forename: D
authors.initials: D
authors.lastname: Monti
authors.forename: L
authors.initials: L
authors.lastname: Troiano
authors.forename: M
authors.initials: M
authors.lastname: Nasi
authors.forename: A
authors.initials: A
authors.lastname: Cossarizza
authors.forename: C
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D017209:Apoptosis; D002999:Clone Cells; D004272:DNA, Mitochondrial / Q000032:analysis; D018432:Drug Resistance, Multiple / Q000235:genetics; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D018922:HL-60 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis
chemical_list: D004272:DNA, Mitochondrial; D018840:HSP70 Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione