siAKR1C3@PPA complex nucleic acid nanoparticles inhibit castration-resistant prostate cancer in vitro

Abstract

IntroductionAKR1C3, 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.MethodssiAKR1C3@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.ResultsAptamer-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.ConclusionWe concluded that siAKR1C3@PPA may arrest the cell cycle and affect cell proliferation.

Recent advances in multifunctional dendrimer‐based complexes for cancer treatment

“…Such a complex nanosystem was targeted into tumor tissues by an amplified EPR effect and processed by dual‐modal computed tomography/magnetic resonance imaging for pancreatic tumors in vivo. As it is known that AKR1C3 is an androgenic enzyme affecting androgen biosynthesis and promoting prostate cancer growth in vitro, Cui et al (2022) researched a nanocomplex consisting of PEG3500, the PAMAM dendrimer, and an aptamer‐PSMA for siRNA delivery to fight AKR1C3. This nanocomplex efficiently delivered siAKR1C3 into PSMA‐positive (prostate‐specific membrane antigen ‐ positive) prostate cancer cells and downregulated AKR1C3.…”

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies

“…The complex formed by AKR1C3 and AR-V7 was found to be crucial for tumor growth in CRPC cells after ADT treatment, suppressing the protein degradation of both components (Wang et al, 2020a). Targeting AKR1C3 using aptamer-PSMA guided siAKR1C3@PPA that is assembled from PEG3500, PAMAM, and siRNA for AKR1C3 into PSMA-positive PCa cells, resulting in specific downregulation of AKR1C3 and potential cell cycle arrest (Cui et al, 2022). Additionally, HEXIM1 was identified as a regulator, downregulating AKR1C3 expression in breast and PCa cells, affecting hormone production, gene expression, and cell proliferation (Mozar et al, 2022).…”