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Departments of Veterinary Physiology and Pharmacology (M.A., S.S.) and Veterinary Pathobiology (R.S.), Texas A&M University, College Station, Texas
Sequence-specific small interfering RNA (siRNA) duplexes can be used for
gene silencing in mammalian cells and as mechanistic probes for determining
gene function. Transfection of siRNAs for the aryl hydrocarbon receptor (AhR)
and AhR nuclear translocator (ARNT) mRNAs in MCF-7 breast cancer cells
resulted in a 60 to 80% decrease in levels of AhR and ARNT proteins in
whole-cell extracts and decreased binding of nuclear extracts to
32P-labeled dioxin-responsive element. siRNA for the AhR also
decreased 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1
protein, CYP1A1-dependent activity, and luciferase activity in cells
transfected with an Ah-responsive construct. 17
-Estradiol (E2) induces
proliferation of MCF-7 cells through enhanced G0/G1
S phase progression, and this response is inhibited in cells cotreated
with E2 plus TCDD. The effects of TCDD on E2-induced cell-cycle progress were
partially blocked in MCF-7 cells transfected with siRNA for AhR. The results
also indicated that siRNA-dependent decreases in AhR protein in MCF-7 cells
were accompanied by increased G0/G1 S phase
progression, suggesting a growth-inhibitory role for the
"endogenous" AhR. Surprisingly, TCDD alone induced
G0/G1 S phase progression and exhibited
estrogenic activity in MCF-7 cells transfected with siRNA for the AhR. In
contrast, degradation of the AhR in HepG2 liver cancer cells resulted in
decreased G0/G1 S phase progression, and this was
accompanied by decreased expression of cyclin D1, cyclin E, cyclin-dependent
kinase 2 (cdk2), and cdk4. In the absence of ligand, the AhR exhibits
growth-inhibitory (MCF-7) and growth-promoting (HepG2) activity that is cell
context-dependent.
Received November 8, 2002; accepted March 7, 2003.
Address correspondence to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Veterinary Research Building 409, College Station, TX 77843-4466. E-mail: ssafe{at}cvm.tamu.edu
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