Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Abstract

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

The therapeutic potential of targeting tryptophan catabolism in cancer

“… 74 Furthermore, AHR activation was shown to promote resistance against several cancer drugs, including BRAF inhibitors (BRAFi), 66 tyrosine kinase inhibitors targeting the EGFR 106 and chemotherapeutic agents. 107 – 109 Recently, Kyn-mediated AHR activation was reported to promote proliferation of MYC-dependent cancer cells. 110 The AHR pathway therefore constitutes a key immunoregulatory and cancer-promoting mechanism downstream of Trp catabolism.…”

Targeting lipid droplet lysophosphatidylcholine for cisplatin chemotherapy

“…LDLR knockdown cells or overexpression clone cells were engineered by the stable transfection of human LDLR cDNA (pLenti-C-mGFP-LDLR, RC200006L2; OriGENE) or pLKO.1-shLDLR (targeting sequence: 5′-GGG CGA CAG ATG CGA AAG AAA) 10 and then selected after exposure to puromycin (10 μmol/L) for a month. [25][26][27] The pLKO-shLuciferase plasmids were obtained from the National RNAi Core Facility Platform (Institute of Molecular Biology or Genome Research Center, Academia Sinica, supported by the National Core Facility Program for Biotechnology; grant number: NSC107-2319-B-001-002). The lentiviral production and infection procedures used in this study followed those reported previously.…”

A review of the effects and molecular mechanisms of dimethylcurcumin (ASC‐J9) on androgen receptor‐related diseases

“…Androgen receptor signalling is reported to participate in proliferation of ovarian cancer and correlate with chemotherapeutic drug resistance in ovarian cancer. It is reported that paclitaxel could enhance AR transcriptional activity and bind to alternative androgen responsive element in the proximal promoter region of ABCG2, leading to increased ABCG2 expression and paclitaxel resistance in epithelial ovarian cancer (EOC) serous subtype cell lines (Chung et al, 2019). Targeting AR with ASC-J9 resensitizes paclitaxel-resistant EOC upon paclitaxel treatment both in vitro and in vivo.…”