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Androgen receptor variant-7 regulation by tenascin-c induced src activation
Rintu Thomas1, John Michael Jerome2, Truong D Dang2
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Rintu.Thomas@bcm.edu.
Cell Communication and Signaling : CCS
|August 10, 2022
Summary
Prostate cancer cells in bone metastases interact with preosteoblasts and TNC, upregulating AR-V7 expression. TNC-induced Src activation drives AR-V7 stability and nuclear localization, contributing to lethal castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bone metastatic prostate cancer often progresses to lethal castration-resistant prostate cancer (CRPC) despite androgen-targeted therapy.
- Androgen Receptor Splice Variant 7 (AR-V7) expression is a key mechanism of CRPC resistance.
- Tenascin-C (TNC) is an extracellular matrix protein implicated in prostate cancer progression and bone metastasis.
Purpose of the Study:
- To investigate the mechanisms regulating AR-V7 expression in prostate cancer cells within the osteogenic microenvironment.
- To elucidate the role of TNC and its interaction with preosteoblasts in AR-V7 regulation.
Main Methods:
- Utilized prostate cancer/preosteoblast heterotypical organoids for immunofluorescence and gene expression analysis (RT-qPCR).
- Assessed AR-V7 regulation and TNC-induced signaling pathways in prostate cancer cells cultured on TNC using RT-qPCR, Western blotting, and cycloheximide chase assays.
- Employed siRNA and small molecular inhibitors to target identified signaling pathways and AR-V7/TNC effectors.
Main Results:
- Preosteoblast interaction upregulated both TNC and AR-V7 in prostate cancer cells, with AR-V7 suppressed by testosterone and elevated by enzalutamide.
- TNC-induced Src activation was found to regulate AR-V7 expression, stability, and nuclear localization.
- Targeting TNC, Src knockdown, or Src inhibition reduced AR-V7 levels; activated Src and AR-V7 reciprocally upregulated autocrine TNC expression.
Conclusions:
- Prostate cancer cell interactions with the osteogenic microenvironment, including cellular and ECM components like TNC, are critical for regulating AR-V7.
- The TNC-Src signaling axis plays a significant role in AR-V7 expression and stability, contributing to CRPC development.
- Understanding these interactions provides insights into mechanisms driving metastatic CRPC and potential therapeutic targets.
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