Cisplatin Inhibits AhR Activation

Abstract

The AhR binds to contain ligands, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin, 3-methylcholantrene, or β-naphthoflavone. The activation mechanism of AhRis not yet fully understood, but it is known that AhR associates with the molecular chaperone HSP90 in the cytoplasm. There are a few reports about the association or dissociation of AhR and HSP90, and which domain of HSP90 binds to AhR. We reported the association and activation mechanisms between HSP90 and AhR-PAS or AhR-bHLH. In the current study, we found that cisplatin inhibits the AhR activation. Although ATP and 17-DMAG have no effect on the dissociation of HSP90 from AhR, some contents of HSP90 were dissociated from AhR in the presence of cisplatin. We could detect the increase of CYP1A in the presence of 3-MC. On the contrary, the induction of CYP1A1 was inhibited in the presence of cisplatin. We couldn't detect AhR in the HeLa cell soluble fraction in the presence of 50 μM cisplatin. In the presence of MG-132, we could detect AhR. These results suggested that AhR was dissociated from the HSP90 chaperone complex and processed during the protein proteasome degradation system in the presence of cisplatin.

Acquired ABC-transporter overexpression in cancer cells: transcriptional induction or Darwinian selection?

“…Example: Exposure of cancer cells to cisplatin can increase the expression of ABCG2/BCRP (Vesel et al 2017 ). However, cisplatin is not transported by BCRP (Yuan et al 2009 ) and it does not activate the main ABCG2 regulator AhR (Sasaki-Kudoh et al 2018 ). In consequence, ABCG2/BCRP overexpression upon cisplatin treatment likely is a non-related coincidence.…”

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

“…Thus, as would be predicted from the studies on ABCG2 and ALDH1, AHR inhibitors increased the sensitivity of ER + and ER - breast carcinoma cells to Adriamycin and Paclitaxel [ 162 , 199 ], oral cancer cells to Cisplatin [ 106 , 199 ] and choriocarcinoma cells to Methotrexate [ 197 ], directly connecting AHR-driven CSCs to cancer treatment outcomes. With regard to these studies, the ability of some of the chemotherapeutics (e.g., Cisplatin) to reduce AHR signaling in and of themselves, may have contributed to the increased effectiveness of the combination of AHR inhibitor and chemotherapeutics [ 205 ]. That said, Paclitaxel and Adriamycin have been shown to enhance AHR expression in MDA-MB-231 breast cancer cells [ 206 ] and AHR activity in cardiomyocytes [ 206 ], results that one would have expected would lead to a reduction in efficacy of a chemotherapeutic plus AHR inhibitor regimen.…”

The components of the AhR‐molecular chaperone complex differ depending on whether the ligands are toxic or non‐toxic

“…The full-length human AhR, human HSP90, human XAP2, and human p23 proteins were purified as described previously [17][18][19][20].…”

“…In the case of dioxin ligands such as 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD), AhR is known to form AhR‐HSP90‐p23‐XAP2 (hepatitis B Virus X‐associated protein 2, also known as aryl hydrocarbon receptor interacting protein, AIP) complexes in the cytoplasm and to induce the xenobiotic‐metabolizing enzyme as a member of the cytochrome P450 family of drug‐metabolizing enzymes, CYP1A1, CYP1A2, and CYP1B1 after nuclear transfer [12–16]. Thus, the mechanism of activation of AhR by molecular chaperone complexes in the case of toxic ligands has been well studied and we have also reported on the AhR‐molecular chaperone complex [17–20]. However, the activation mechanism of AhR by molecular chaperone complexes in the case of non‐toxic ligands is not fully understood.…”