Related Experiment Video
Updated: Jun 29, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Hsa_circ_0003258 drives serine biosynthesis and docetaxel resistance in prostate cancer by enhancing IGF2BP3-mediated
Shengdong Ge1, Xiaofeng Liu2, Xianzi Zeng2
1Department of Urology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong 510900, China; Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Background:
Docetaxel (DTX)-based therapy remains first-line treatment for advanced prostate cancer (PCa), yet its efficacy is often compromised by chemoresistance. Emerging evidence highlights that circular RNAs (circRNAs) contribute to the development of chemoresistance, but their specific functions in DTX-resistant PCa remain poorly understood.
Methods:
By integrating molecular biology, cell biology, and immunology approaches, we investigated the mechanism by which hsa_circ_0003258 drives DTX resistance in PCa.
Results:
We identified that hsa_circ_0003258 was significantly elevated in DTX-resistant patients of PCa. Functional experiments confirmed that hsa_circ_0003258 enhances DTX resistance both in vitro and in vivo by promoting cancer stem-like properties, independent of its linear transcript. Mechanistically, hsa_circ_0003258 directly bound the RRMs and KH1 domains of IGF2BP3 via its CAUU motif, augmenting the non-competitive interaction between IGF2BP3's KH4 domain and the 3'UTR of PSAT1 mRNA. This led to increased PSAT1 mRNA stability and activation of the serine biosynthesis, thereby reinforcing stemness and driving DTX resistance of PCa. To explore therapeutic potential, we engineered targeted nanoliposomes (HA-LNP@si-hsa_circ_0003258/cy7) which selectively accumulated in PCa xenografts and significantly inhibited tumor growth in combination with DTX. Co-treatment with Bix, a G9a inhibitor previously reported to suppress PSAT1 expression, further enhanced the antitumor efficacy of this combination, suggesting a potential synergistic therapeutic effect.
Conclusion:
Our findings reveal a novel hsa_circ_0003258/IGF2BP3/PSAT1 axis that enhances de novo serine synthesis and drives DTX resistance in PCa, highlighting this pathway as a promising therapeutic target.
Insights
Circular RNAs (circRNAs) like hsa_circ_0003258 promote docetaxel resistance in prostate cancer (PCa) by enhancing stemness. Targeting this circRNA offers a potential therapeutic strategy for overcoming chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Docetaxel (DTX) is a first-line treatment for advanced prostate cancer (PCa).
- Chemoresistance significantly limits the efficacy of DTX therapy in PCa.
- Circular RNAs (circRNAs) are implicated in chemoresistance, but their role in DTX-resistant PCa is unclear.
Purpose of the Study:
- To investigate the mechanism by which hsa_circ_0003258 contributes to DTX resistance in PCa.
- To explore the therapeutic potential of targeting hsa_circ_0003258 in DTX-resistant PCa.
Main Methods:
- Integrated molecular biology, cell biology, and immunology.
- Investigated hsa_circ_0003258 expression and function in DTX-resistant PCa models.
- Utilized targeted nanoliposomes for therapeutic intervention.
Main Results:
- hsa_circ_0003258 is significantly elevated in DTX-resistant PCa patients.
- hsa_circ_0003258 promotes DTX resistance by enhancing cancer stem-like properties via the IGF2BP3/PSAT1 axis.
- Engineered nanoliposomes targeting hsa_circ_0003258 combined with DTX showed significant tumor inhibition.
Conclusions:
- A novel hsa_circ_0003258/IGF2BP3/PSAT1 axis drives DTX resistance in PCa.
- This pathway enhances de novo serine synthesis, promoting stemness and chemoresistance.
- The identified axis represents a promising therapeutic target for overcoming DTX resistance in prostate cancer.
