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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
siAKR1C3@PPA complex nucleic acid nanoparticles inhibit castration-resistant prostate cancer in vitro
Xiaoli Cui1, Zhou Yao1, Tianyu Zhao1
1Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Introduction:
AKR1C3, as a crucial androgenic enzyme, implicates the androgen biosynthesis and promoting prostate cancer cell growth in vitro. This study provides a new gene therapy strategy for targeting AKR1C3 to treat castration-resistant prostate cancer.
Methods:
siAKR1C3@PPA is assembled from PEG3500, PAMAM, Aptamer-PSMA, and siRNA for AKR1C3. We analyzed the relationship between AKR1C3 expression and the survival rate of prostate cancer patients based on the GEPIA online database to perform disease-free survival, and found that AKR1C3 may be an important factor leading to poor prognosis in prostate cancer. Considering AKR1C3 as a therapeutic target for castration-resistant prostate cancer, we constructed a complex nucleic acid nanoparticle, siAKR1C3@PPA to investigate the inhibitory effect on castration-resistant prostate cancer.
Results:
Aptamer-PSMA acts as a target to guide siAKR1C3@PPA into PSMA-positive prostate cancer cells and specifically down regulate AKR1C3. Cyclin D1 was decreased as a result of siAKR1C3@PPA treatment. Changes in Cyclin D1 were consistent with decreased expression of AKR1C3 in LNCaP-AKR1C3 cells and 22RV1 cells. Furthermore, in the LNCaP-AKR1C3 group, 1070 proteins were upregulated and 1015 proteins were downregulated compared to the LNCaP group according to quantitative 4D label-free proteomics. We found 42 proteins involved in cell cycle regulation. In a validated experiment, we demonstrated that PCNP and CINP were up-regulated, and TERF2 and TP53 were down-regulated by western blotting.
Conclusion:
We concluded that siAKR1C3@PPA may arrest the cell cycle and affect cell proliferation.
Insights
This study developed siAKR1C3@PPA, a novel gene therapy targeting AKR1C3 (a key enzyme in prostate cancer) for castration-resistant prostate cancer. Treatment with siAKR1C3@PPA demonstrated potential to arrest the cell cycle and inhibit cancer cell proliferation.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- AKR1C3 is a crucial androgenic enzyme promoting prostate cancer growth.
- High AKR1C3 expression correlates with poor prognosis in prostate cancer patients.
- Targeting AKR1C3 presents a potential therapeutic strategy for castration-resistant prostate cancer.
Purpose of the Study:
- To develop and evaluate a novel gene therapy strategy targeting AKR1C3.
- To investigate the efficacy of siAKR1C3@PPA in inhibiting castration-resistant prostate cancer.
- To explore the molecular mechanisms underlying the anti-cancer effects of siAKR1C3@PPA.
Main Methods:
- siAKR1C3@PPA nanoparticles were constructed using PEG3500, PAMAM, Aptamer-PSMA, and siRNA targeting AKR1C3.
- AKR1C3 expression and patient survival data were analyzed using the GEPIA online database.
- The inhibitory effect of siAKR1C3@PPA on castration-resistant prostate cancer cells was assessed, including proteomic analysis and western blotting.
Main Results:
- siAKR1C3@PPA specifically targeted and downregulated AKR1C3 in PSMA-positive prostate cancer cells.
- Treatment led to decreased Cyclin D1 levels, consistent with AKR1C3 downregulation.
- Proteomic analysis revealed significant alterations in proteins involved in cell cycle regulation, with specific up- and down-regulation of key proteins like PCNP, CINP, TERF2, and TP53.
Conclusions:
- siAKR1C3@PPA shows promise as a gene therapy agent for castration-resistant prostate cancer.
- The therapy may exert its effects by arresting the cell cycle and influencing cell proliferation.
- Further investigation into the identified protein changes could elucidate detailed therapeutic mechanisms.
