Ability to acquire drug resistance arises early during the tumorigenesis process.
Resistance to chemotherapy is one of the principal causes of cancer mortality and is generally considered a late event in tumor progression. Although cellular models of drug resistance have been useful in identifying the molecules responsible for conferring drug resistance, most of these cellular models are derived from cell lines isolated from patients at a late stage in cancer progression. To ask at which stage in the tumorigenic progression does the cell gain the ability to acquire drug resistance, we generated a series of pre-tumorigenic and tumorigenic cells from human embryonic skin fibroblasts by introducing, sequentially, the catalytic subunit of telomerase, SV40 large T and small T oncoproteins, and an oncogenic form of ras. We show that the ability to acquire multidrug resistance (MDR) can arise before the malignant transformation stage. The minimal set of changes necessary to obtain pre-tumorigenic drug-resistant cells is expression of telomerase and inactivation of p53 and pRb. Thus, the pathways inactivated during tumorigenesis also confer the ability to acquire drug resistance. Microarray and functional studies of drug-resistant pre-tumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pre-tumorigenic cell model.
Yagüe
Ernesto
E
Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Du Cane Road, Lonson, UK.
Arance
Ana
A
Kubitza
Loïc
L
O'Hare
Michael
M
Jat
Parmjit
P
Ogilvie
Caroline M
CM
Hart
Ian R
IR
Higgins
Christopher F
CF
Raguz
Selina
S
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D015870:Gene Expression; D006801:Humans; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012879:Skin Physiological Phenomena / Q000187:drug effects / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000952:Antigens, Polyomavirus Transforming; D027361:Organic Anion Transporters; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C509186:TERT protein, human; D019098:Telomerase; D018631:ras Proteins