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AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production

Oncogene (2024)Cite this article

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Abstract

Androgen Receptor (AR) activity in prostate stroma is required to maintain prostate homeostasis. This is mediated through androgen-dependent induction and secretion of morphogenic factors that drive epithelial cell differentiation. However, stromal AR expression is lost in aggressive prostate cancer. The mechanisms leading to stromal AR loss and morphogen production are unknown. We identified TGFβ1 and TNFα as tumor-secreted factors capable of suppressing AR mRNA and protein expression in prostate stromal fibroblasts. Pharmacological and RNAi approaches identified NF-κB as the major signaling pathway involved in suppressing AR expression by TNFα. In addition, p38α- and p38δ-MAPK were identified as suppressors of AR expression independent of TNFα. Two regions of the AR promoter were responsible for AR suppression through TNFα. FGF10 and Wnt16 were identified as androgen-induced morphogens, whose expression was lost upon TNFα treatment and enhanced upon p38-MAPK inhibition. Wnt16, through non-canonical Jnk signaling, was required for prostate basal epithelial cell survival. These findings indicate that stromal AR loss is mediated by secreted factors within the TME. We identified TNFα/TGFβ as two possible factors, with TNFα mediating its effects through NF-κB or p38-MAPK to suppress AR mRNA transcription. This leads to loss of androgen-regulated stromal morphogens necessary to maintain normal epithelial homeostasis.

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Fig. 1: TNFα and TGFβ suppress AR expression.
Fig. 2: TNFα activates NF-κB to mediate TNFα-induced AR suppression.
Fig. 3: p38-MAPK suppresses basal levels of AR expression.
Fig. 4: NF-κB and p38-MAPK target RelA and ATF binding regions in the AR promoter to control AR expression.
Fig. 5: AR suppression in primary stromal cells.
Fig. 6: FGF10 and Wnt16 are stromal AR targets suppressed by TNFα and p38-MAPK.
Fig. 7: Wnt16 maintains prostate basal cell survival via Jnk signaling.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Acknowledgements

We thank Carol Kepler in the Tissue Acquisition and Cellular Molecular Analysis Shared Resource (TACMASR) for helping to secure primary prostate stromal cells, Dr. Sander Frank for his cloning expertise, and Dr. Ghassan Mouneimne for critical editing. ST, NS, BC, LJ, YZ, and CKM were supported by funding from NIH/NCI MPI R01 CA254200 and TACMASR by P30 CA023075.

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Authors and Affiliations

  1. Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA

    Shekha Tahsin & Cindy K. Miranti

  2. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

    Neha S. Sane, Brent Cernyar & Cindy K. Miranti

  3. Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ, USA

    Linan Jiang & Yitshak Zohar

  4. University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    Yitshak Zohar, Benjamin R. Lee & Cindy K. Miranti

  5. Department of Urology, University of Arizona, Tucson, AZ, USA

    Benjamin R. Lee

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ST was responsible for designing, carrying out, and interpreting the experiments, as well as the primary writer of the manuscript. NSS and BC designed and carried out experiments and helped edit the manuscript. LJ and YZ assisted with interpretation of data and editing the manuscript. BRL contributed patient tissues and helped with manuscript editing. CM directed the project, assisted in data interpretation, did manuscript writing and editing, and is the contributing author.

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Correspondence to Cindy K. Miranti.

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Tahsin, S., Sane, N.S., Cernyar, B. et al. AR loss in prostate cancer stroma mediated by NF-κB and p38-MAPK signaling disrupts stromal morphogen production. Oncogene (2024). https://doi.org/10.1038/s41388-024-03064-7

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