TY - JOUR
T1 - Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs
AU - Nayak, Mamatha S.
AU - Yang, Jin Ming
AU - Hait, William N.
PY - 2007/6/15
Y1 - 2007/6/15
N2 - A single nucleotide polymorphism (SNP) SNP309 (T→G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer and decreases the response ofcancer cells to certain forms of treatment, such as radiation therapy and DNA-damaging drugs. Topoisomerase II (TopoII)-targeting agents are commonly used chemotherapeutic drugs with a broad spectrum ofactivity. However, resistance to TopoII poisons limits their effectiveness. We show that MDM2 SNP309 rendered a panel of cancer cell lines that are homozygous for SNP309 selectively resistant ( ≃ 10-fold) to certain TopoII-targeting chemotherapeutic drugs (etoposide, mitoxantrone, amsacrine, and ellipticine). The mechanism underlying this observation was Mdm2-mediated down-regulation of TopoII; on drug exposure, MDM2 bound to TopoII and resulted in decreased cellular enzyme content. Knockdown of MDM2 by RNA interference stabilized TopoIIα and decreased resistance to TopoII-targeting drugs. Thus, MDM2 SNP309 (T→G) may represent a relatively common, previously unappreciated determinant of drug sensitivity. Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy.
AB - A single nucleotide polymorphism (SNP) SNP309 (T→G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer and decreases the response ofcancer cells to certain forms of treatment, such as radiation therapy and DNA-damaging drugs. Topoisomerase II (TopoII)-targeting agents are commonly used chemotherapeutic drugs with a broad spectrum ofactivity. However, resistance to TopoII poisons limits their effectiveness. We show that MDM2 SNP309 rendered a panel of cancer cell lines that are homozygous for SNP309 selectively resistant ( ≃ 10-fold) to certain TopoII-targeting chemotherapeutic drugs (etoposide, mitoxantrone, amsacrine, and ellipticine). The mechanism underlying this observation was Mdm2-mediated down-regulation of TopoII; on drug exposure, MDM2 bound to TopoII and resulted in decreased cellular enzyme content. Knockdown of MDM2 by RNA interference stabilized TopoIIα and decreased resistance to TopoII-targeting drugs. Thus, MDM2 SNP309 (T→G) may represent a relatively common, previously unappreciated determinant of drug sensitivity. Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy.
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U2 - 10.1158/0008-5472.CAN-06-4533
DO - 10.1158/0008-5472.CAN-06-4533
M3 - Article
C2 - 17575151
AN - SCOPUS:34250888210
SN - 0008-5472
VL - 67
SP - 5831
EP - 5839
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -