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Proteomic Analysis Reveals AMPKα-Mediated Antiandrogen Resistance via Ferroptosis Suppression in Prostate Cancer
Masaki Shiota1, Tokiyoshi Tanegashima1, Takahiko Hajime1
1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract:
Metastatic prostate cancer often develops resistance to second-generation androgen receptor pathway inhibitors (ARPIs) such as enzalutamide and darolutamide, limiting their long-term efficacy. In this study, we applied the high-precision absolute quantitative proteomics platform iMPAQT to comprehensively profile protein expression changes in multiple prostate cancer cell lines and their ARPI-resistant derivatives. Our analysis revealed consistent dysregulation of ferroptosis suppressor pathway alongside elevated phosphorylation of AMPKα signaling in resistant cells. While antiandrogen treatment increased lipid peroxidation in parental cells, resistant cells adapted by upregulating key ferroptosis-regulating proteins including FTH1 and GPX4, thereby evading ferroptosis. Functional assays demonstrated that the GPX4 inhibitor RSL3 selectively suppressed proliferation of resistant cells more potently than parental cells. Moreover, combination treatment with AMPKα inhibitors enhanced the anti-proliferative effect of RSL3. These findings suggest that ferroptosis suppression is a critical mechanism underpinning resistance to ARPIs in prostate cancer. Targeting pathways involved in ferroptosis regulation in combination with AMPKα inhibitors holds promise for overcoming therapeutic resistance and improving patient outcomes.
Insights
Prostate cancer develops resistance to treatments by suppressing ferroptosis. Targeting ferroptosis and AMPKα signaling may overcome this resistance, improving outcomes for metastatic prostate cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- Metastatic prostate cancer frequently develops resistance to androgen receptor pathway inhibitors (ARPIs), such as enzalutamide and darolutamide.
- This resistance limits the long-term effectiveness of these crucial therapies.
Purpose of the Study:
- To investigate the molecular mechanisms underlying ARPI resistance in prostate cancer.
- To identify potential therapeutic targets for overcoming ARPI resistance.
Main Methods:
- Utilized the iMPAQT platform for high-precision absolute quantitative proteomics.
- Analyzed protein expression changes in ARPI-sensitive and resistant prostate cancer cell lines.
- Performed functional assays using ferroptosis and AMPKα pathway modulators.
Main Results:
- Resistant prostate cancer cells exhibited dysregulation of the ferroptosis suppressor pathway and increased AMPKα phosphorylation.
- Resistant cells upregulated ferroptosis regulators (FTH1, GPX4) to evade ferroptosis induced by antiandrogen treatment.
- GPX4 inhibition (RSL3) selectively reduced proliferation in resistant cells, an effect enhanced by AMPKα inhibitors.
Conclusions:
- Ferroptosis suppression is a key mechanism driving ARPI resistance in prostate cancer.
- Combination therapy targeting ferroptosis regulation and AMPKα signaling shows promise for overcoming treatment resistance and improving patient outcomes.
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