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Second generation androgen receptor antagonist, TQB3720 abrogates prostate cancer growth via AR/GPX4 axis activated
Zhongqing Zhang1,2, Tianlei Xie1,2, Shun Zhang1,3
1Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Abstract:
Purpose: Prostate cancer (PCa) poses a great threat to humans. The study aimed to evaluate the potential of TQB3720 in promoting ferroptosis to suppress prostate cancer, providing a theoretical basis for PCa therapy. Methods: PCa cells and nude mice models were divided into TQB3720, enzalutamide (ENZ), and control groups. Sulforhodamine B assay, colony formation assessment, organoids culture system, and the CCK8 assay were used for detecting proliferation. Western blot assay was processed to detect the expression of androgen receptor (AR), ferroptosis, and apoptosis-related genes. Flow cytometry was applied to measure the intracellular ROS levels. ELISA was performed to determine the cellular oxidized glutathione (GSSG) and malondialdehyde (MDA) levels. RT-qPCR was conducted to detect the mRNA expression of genes in AR signaling. BODIPYTM™ 581/591 was processed for detection of intracellular lipid peroxidation levels. The interaction of AR with other translational factor complex proteins was explored using Co-immunoprecipitation (Co-IP), and the chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of AR-involved translational complex to downstream genes promoter. Luciferase reporter assay was conducted to examine the translation activity of GPX4 promoter, and immunohistochemistry (IHC) was conducted to analyze the levels of c-MYC, Ki-67 and AR in TQB3720-treated cancer tissues. Results: Here, we found TQB3720 inhibits the growth of prostate cancer in vitro and in vivo. TQB3720 treatment induced intracellular levels of GSSG and MDA significantly, by which hints AR antagonist caused ferroptosis-related cell death. Moreover, molecular evidence shown TQB3720 regulates downstream of AR signaling by binding AR resulting in inhibition of AR entry into the nucleus. Additional, we also proved that TQB3720 abrogates the interaction between AR and SP1 and leads to decrease GPX4 transcription. Conclusion: TQB3720 promotes ferroptosis in prostate cancer cells by reducing the AR/SP1 transcriptional complex binding to GPX4 promoter. As a result, it is suggested to be a potential drug for clinic prostate cancer treatment.
Insights
TQB3720 inhibits prostate cancer growth by inducing ferroptosis. This novel drug candidate disrupts the AR/SP1 complex, reducing GPX4 transcription and offering a new therapeutic avenue for prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (PCa) remains a significant global health concern.
- Current therapies often face challenges with resistance and efficacy.
- Targeting specific molecular pathways like ferroptosis presents a promising therapeutic strategy.
Purpose of the Study:
- To investigate the efficacy of TQB3720 in suppressing prostate cancer.
- To elucidate the mechanism by which TQB3720 induces ferroptosis in PCa cells.
- To evaluate TQB3720 as a potential therapeutic agent for PCa.
Main Methods:
- In vitro and in vivo models of prostate cancer (cell lines, nude mice).
- Assays for cell proliferation (SRB, CCK8, colony formation), ferroptosis markers (GSSG, MDA, lipid peroxidation), apoptosis, and ROS.
- Molecular techniques including Western blot, RT-qPCR, Co-IP, ChIP, and luciferase reporter assays to analyze Androgen Receptor (AR) signaling and gene transcription.
- Immunohistochemistry (IHC) for protein expression analysis.
Main Results:
- TQB3720 demonstrated significant inhibition of prostate cancer growth both in vitro and in vivo.
- TQB3720 treatment led to increased intracellular GSSG and MDA levels, indicating ferroptosis induction.
- TQB3720 was shown to regulate AR signaling by inhibiting AR nuclear entry and abrogating the AR/SP1 interaction, thereby decreasing GPX4 transcription.
Conclusions:
- TQB3720 effectively suppresses prostate cancer by promoting ferroptosis.
- The mechanism involves the disruption of the AR/SP1 transcriptional complex binding to the GPX4 promoter.
- TQB3720 shows potential as a novel therapeutic drug for clinical prostate cancer treatment.
