The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells

Abstract

Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer.

Enzalutamide-Resistant Progression of Castration-Resistant Prostate Cancer Is Driven via the JAK2/STAT1-Dependent Pathway

“…This suggested that ARv7 might be involved in the cross-resistance between ENZ and ABI. Although ARv7-positive patients showed much worse treatment responses to NHT (Armstrong et al, 2020;Wang et al, 2020a;Wang et al, 2020b), the clinical data analysis demonstrated that these patients could significantly benefit from taxane chemotherapy, which was possibly related to the higher activity of the E2F1/AR3 feed-forward loop (Xu et al, 2020). The CXCR7-JAK2/STAT1 signaling pathway, as an independent AR bypass pathway, may also participate in resistance to androgen target therapy.…”

Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness

“…In this context, Liu et al proved that AF (1 µM) promoted androgen receptor protein degradation and inhibited androgen receptor transcription in two androgen receptor‐positive cell lines, LNcap and 22RV1 125 . Xu et al demonstrated that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibited the growth of prostate cancer cells that are resistant to either single drug 126 . Thus, the authors generated a cell line resistant to both DTX and ENZ and demonstrated that AF could overcome resistance by inhibiting the growth of these drug‐resistant prostate cancer cells both in vitro and in vivo.…”

“… 125 Xu et al demonstrated that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibited the growth of prostate cancer cells that are resistant to either single drug. 126 Thus, the authors generated a cell line resistant to both DTX and ENZ and demonstrated that AF could overcome resistance by inhibiting the growth of these drug‐resistant prostate cancer cells both in vitro and in vivo.…”

Comprehensive analysis of the functional and prognostic value of E2F transcription factors in human prostate cancer through data mining and experimental validation

“…Yang et al demonstrated that high expression of E2F1 is associated with unfavorable prognosis in PCa cells ( 32 ). The study by Xu et al showed that E2F1 was markedly up in cancer and plays a key role in cellular inhibition when it is down-regulated ( 33 ). Qi et al showed that in PCa cells, E2F1 participates in epithelial mesenchymal transition (EMT) ( 34 ).…”