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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
ADAMTS9-AS2 Disrupts Docetaxel-Resistance in Castration-Resistant Prostate Cancer via Stemness Suppression and
Ji Liu1,2, Yan Gao3, Yadong Guo1,2
1Department of Urology, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, P. R. China.
Abstract:
Castration-resistant prostate cancer (CRPC) chemotherapy resistance remained a significant clinical challenge. Prostate tumor stem cells (PCSCs) played a crucial role in chemotherapy resistance, but the underlying mechanisms were not fully understood. This study investigated how ADAMTS9-AS2 reduced chemotherapy resistance in CRPC through a dual mechanism and explored the potential of polymeric materials targeting PCSCs and enhancing chemotherapy sensitivity. Key regulatory molecules of PCSCs were identified through mRNAsi-based multi-center patient cohorts. The effect of ADAMTS9-AS2 on reducing docetaxel resistance in CRPC was assessed, and its mechanisms were further explored using in vitro and in vivo experiments. Finally, polymeric materials containing TGF-β inhibitor, ferroptosis inducer, and miR-182-5p inhibitor were used to target PCSCs to improve chemotherapy sensitivity. ADAMTS9-AS2 reduced CRPC chemotherapy resistance through dual mechanisms: (1) regulating FOXF2/TGF-β2 axis to suppress PCSCs stemness; (2) encoding a short peptide that competitively retained more SLC7A11 in the cytoplasm than on the cytomembrane, thus promoting ferroptosis. Furthermore, polymeric materials targeting PCSCs significantly enhanced docetaxel sensitivity and inhibited tumor progression. ADAMTS9-AS2 delayed docetaxel resistance by suppressing CRPC stemness and inducing ferroptosis. The use of polymeric materials targeting PCSCs offered a novel strategy to overcome CRPC chemotherapy resistance.
Insights
ADAMTS9-AS2 combats chemotherapy resistance in castration-resistant prostate cancer (CRPC) by suppressing prostate tumor stem cells (PCSCs) and promoting ferroptosis. Novel polymeric materials targeting PCSCs further enhance chemotherapy sensitivity, offering a new strategy against CRPC.
Area of Science:
- Oncology
- Molecular Biology
- Biomaterials
Background:
- Chemotherapy resistance in castration-resistant prostate cancer (CRPC) is a major clinical hurdle.
- Prostate tumor stem cells (PCSCs) are implicated in CRPC chemotherapy resistance, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of ADAMTS9-AS2 in overcoming docetaxel resistance in CRPC.
- To elucidate the dual mechanisms by which ADAMTS9-AS2 reduces chemotherapy resistance.
- To explore the efficacy of novel polymeric materials targeting PCSCs to enhance chemotherapy sensitivity.
Main Methods:
- Identification of PCSC regulatory molecules using mRNAsi-based multi-center patient cohorts.
- In vitro and in vivo experiments to assess ADAMTS9-AS2's effect on docetaxel resistance.
- Development and application of polymeric materials incorporating TGF-β inhibitor, ferroptosis inducer, and miR-182-5p inhibitor.
Main Results:
- ADAMTS9-AS2 suppresses PCSC stemness via the FOXF2/TGF-β2 axis.
- ADAMTS9-AS2 promotes ferroptosis by influencing SLC7A11 localization.
- Polymeric materials targeting PCSCs significantly improved docetaxel sensitivity and inhibited tumor growth in vivo.
Conclusions:
- ADAMTS9-AS2 mitigates CRPC chemotherapy resistance through PCSC stemness suppression and ferroptosis induction.
- Targeting PCSCs with specialized polymeric materials presents a promising therapeutic strategy for overcoming CRPC chemoresistance.
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