Exosomes from PYCR1 knockdown bone marrow mesenchymal stem inhibits aerobic glycolysis and the growth of bladder cancer cells via regulation of the EGFR/PI3K/AKT pathway

Bladder cancer (BC) is a heterogeneous disease, and pyrroline‑5‑carboxylate reductase 1 (PYCR1) can promote the proliferation and invasion of BC cells and accelerate BC progression. In the present study, si‑PYCR1 was loaded into bone marrow mesenchymal stem cell (BMSC)‑derived exosomes (Exos) in BC. First, PYCR1 levels in BC tissues/cells were assessed, and cell proliferation, invasion, and migration were evaluated. Aerobic glycolysis levels (glucose uptake, lactate production, ATP production, and the expression of relevant enzymes) and the EGFR/PI3K/AKT pathway phosphorylation levels were determined. PYCR1‑EGFR interactions were examined by co‑immunoprecipitation experiments. RT4 cells transfected with oe‑PYCR1 were treated with EGFR inhibitor CL‑387785. Exos were loaded with si‑PYCR1 and identified, followed by an assessment of their effects on aerobic glycolysis and malignant cell behaviors. Nude mouse models of xenograft tumors were established by injecting mice with Exo‑si‑PYCR1 and Exo‑si‑PYCR1. PYCR1 was upregulated in BC cells, with the highest expression observed in T24 cells and the lowest expression in RT4 cells. Following PYCR1 knockdown, the malignant behaviors of T24 cells and aerobic glycolysis were decreased, while PYCR1 overexpression in RT4 cells averted these trends. PYCR1 interacted with EGFR, and CL‑387785 inhibited the EGFR/PI3K/AKT pathway and attenuated the effects of PYCR1 overexpression on RT4 cells but had no effect on PYCR1 expression. Exo‑si‑PYCR1 showed stronger inhibitory effects on aerobic glycolysis and on the malignant behaviors of T24 cells than si‑PYCR1. Exo‑si‑PYCR1 blocked xenograft tumor growth and had good biocompatibility. Briefly, PYCR1 knocking loaded by BMSC‑derived Exos suppressed aerobic glycolysis and BC growth via the PI3K/AKT pathway by binding to EGFR.

 

Comments:

This study sounds like a comprehensive exploration of the role of PYCR1 in bladder cancer progression and the potential therapeutic effects of utilizing bone marrow mesenchymal stem cell-derived exosomes (Exos) loaded with si-PYCR1. The findings suggest a promising avenue for potential targeted therapy.

The research seems to focus on several key aspects:

1. **PYCR1 in Bladder Cancer:** The study highlights the elevated expression of PYCR1 in bladder cancer cells and tissues, showcasing its potential as a promoter of cancer cell proliferation and invasion.

2. **Effect on Cell Behaviors:** Knocking down PYCR1 appeared to reduce malignant behaviors in T24 cells while overexpressing it in RT4 cells had the opposite effect, indicating a direct influence of PYCR1 on cancer cell behavior.

3. **Aerobic Glycolysis and EGFR/PI3K/AKT Pathway:** The study explores the impact of PYCR1 on aerobic glycolysis levels and its interaction with the EGFR/PI3K/AKT pathway, suggesting a potential mechanism through which PYCR1 affects cancer progression.

4. **Exosome-Mediated Delivery of si-PYCR1:** Loading si-PYCR1 into bone marrow mesenchymal stem cell-derived exosomes demonstrated stronger inhibitory effects on aerobic glycolysis and malignant behaviors of T24 cells, showcasing a potential therapeutic delivery method.

5. **In Vivo Efficacy:** The study suggests that Exo-si-PYCR1 had inhibitory effects on xenograft tumor growth in nude mouse models, indicating its potential as a viable therapeutic option.

The findings hint at a promising therapeutic strategy for bladder cancer by targeting PYCR1 using Exos loaded with siRNA. The link between PYCR1, EGFR, and the PI3K/AKT pathway opens avenues for further investigation into targeted therapies for bladder cancer.

It’s exciting to see such detailed research that delves into the molecular mechanisms of cancer progression and potential therapeutic interventions. This study could pave the way for further clinical exploration and development of targeted treatments for bladder cancer.

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Cat.No.	Product Name	Information
S7557	CL-387785 (EKI-785)	CL-387785 (EKI-785, WAY-EKI 785) is an irreversible, and selective EGFR inhibitor with IC50 of 370 pM.

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EGFR