Induction of 1C aldoketoreductases and other drug dose-dependent genes upon acquisition of anthracycline resistance.
OBJECTIVE
Recent studies suggest that tumor cells overexpressing aldoketoreductases (AKRs) exhibit increased resistance to DNA damaging agents such as anthracyclines. AKRs may induce resistance to the anthracycline doxorubicin by catalyzing its conversion to the less toxic 13-hydroxy metabolite doxorubicinol. However, it has not been established whether during selection for anthracycline resistance, AKR overexpression in tumor cells can be correlated with the onset or magnitude of drug resistance and with appreciable conversion of anthracyclines to 13-hydroxy metabolites.


RESULTS
Through microarray and quantitative polymerase chain reaction studies involving rigid selection criteria and both correlative discriminate statistics and time-course models, we have identified several genes whose expression can be correlated with the onset and/or magnitude of anthracycline resistance, including AKR1C2 and AKR1C3. Also associated with the onset or magnitude of anthracycline resistance were genes involved in drug transport (ABCB1, ABCC1), cell signaling and transcription (RDC1, CXCR4), cell proliferation or apoptosis (BMP7, CAV1), protection from reactive oxygen species (AKR1C2, AKR1C3, FTL, FTH, TXNRD1, MT2A), and structural or immune system proteins (IFI30, STMN1). As expected, doxorubicin-resistant and epirubicin-resistant cells exhibited higher levels of doxorubicinol than wild-type cells, although at insufficient levels to account for significant drug resistance. Nevertheless, an inhibitor of Akr1c2 (5beta-cholanic acid) almost completely restored sensitivity to doxorubicin in ABCB1-deficient doxorubicin-resistant cells, while having no effect on ABCB1-expressing epirubicin-resistant cells.


CONCLUSIONS
Taken together, we show for the first time that a variety of genes (particularly redox genes such as AKR1C2 and AKR1C3) can be temporally and causally correlated with the acquisition of anthracycline resistance in breast tumor cells.
Veitch
Zachary W
ZW
Department of Biology, Laurentian University, Northern Ontario School of Medicine, Sudbury, Canada.
Guo
Baoqing
B
Hembruff
Stacey L
SL
Bewick
Adam J
AJ
Heibein
Allan D
AD
Eng
Jamei
J
Cull
Stephanie
S
Maclean
David A
DA
Parissenti
Amadeo M
AM
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human