Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer

Abstract

The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclindependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.

Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis

“…These results are consistent with findings in mouse skin carcinogenesis assays that showed that TCDD pretreatment is anticarcinogenic under conditions of low doses of the tumor inducer DMBA [Lesca et al, 1994]. AHR is also expressed at high levels in pancreatic cancer tissues, and TCDD and other AHR agonists inhibit pancreatic cancer cell growth [Koliopanos et al, 2002].…”

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…A number of studies demonstrate AhR expression, usually at notably high levels, in rodent and human tumors (Ma and Whitlock, 1996;Weiss et al, 1996;Ge and Elferink, 1998;Puga et al, 2000Puga et al, , 2002Trombino et al, 2000;Safe, 2001;Koliopanos et al, 2002;Abdelrahim et al, 2003;Hayashibara et al, 2003;Zhang et al, 2003;Thomsen et al, 2004). Furthermore, we have shown in a primary mammary tumor model that much of that AhR resides in the tumor cell nucleus, a result suggestive of constitutive AhR activation in the absence of exogenous ligands (Wang et al, 1995;Trombino et al, 2000).…”

“…This question is all the more significant in light of several studies associating AhR activation with cell growth (Ma and Whitlock, 1996;Weiss et al, 1996;Ge and Elferink, 1998;Puga et al, 2000Puga et al, , 2002Abdelrahim et al, 2003;Ohtake et al, 2003;Thomsen et al, 2004) or apoptosis regulation (Yamaguchi et al, 1997;Matikainen et al, 2001Matikainen et al, , 2002Ryu et al, 2003;Caruso et al, 2004). Indeed, the demonstrable influence of the AhR on at least tumor cell growth has motivated the targeting of this receptor/ transcription factor or its gene targets for cancer therapy (Safe, 2001;Koliopanos et al, 2002;Abdelrahim et al, 2003;Maecker et al, 2003;Zhang et al, 2003).…”

Cobaltous chloride and hypoxia inhibit aryl hydrocarbon receptor-mediated responses in breast cancer cells

“…In addition, chemoprotective natural products including flavonoids, indole-3-carbinol and related heteroaromatics, green tea components, and other polyhydroxy aromatic antioxidants also bind the AhR (Denison, Seidel, Rogers, Ziccardi, Winter, and Heath-Pagliuso, 1998;Denison and Nagy, 2003) and exhibit both AhR agonist and antagonist activities. Ligand-dependent activation of the AhR inhibits growth of ERpositive breast cancer cells , and growth inhibitory effects of AhR agonists have also been observed in pancreatic, prostate and ovarian cancer (Koliopanus et al, 2002;Morrow et al, 2004;Rowlands et al, 1993). These observations have led to development of selective AhR modulators (SAhRMs) as a potential new class of drugs for treatment of these cancers (McDougal, Wormke, Calvin, and Safe, 2001;Safe, McDougal, Gupta, and Ramamoorthy, 2001;Safe and Wormke, 2003).…”