Targeting S6K/NFκB/SQSTM1/Polθ signaling to suppress radiation resistance in prostate cancer Journal Article
| Authors: | Clark, A.; Villarreal, M. R.; Huang, S. B.; Jayamohan, S.; Rivas, P.; Hussain, S. S.; Ybarra, M.; Osmulski, P.; Gaczynska, M. E.; Shim, E. Y.; Smith, T.; Gupta, Y. K.; Yang, X.; Delma, C. R.; Natarajan, M.; Lai, Z.; Wang, L. J.; Michalek, J. E.; Higginson, D. S.; Ikeno, Y.; Ha, C. S.; Chen, Y.; Ghosh, R.; Kumar, A. P. |
| Article Title: | Targeting S6K/NFκB/SQSTM1/Polθ signaling to suppress radiation resistance in prostate cancer |
| Abstract: | In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity. © 2024 The Author(s) |
| Keywords: | signal transduction; protein expression; protein phosphorylation; gene mutation; human cell; overall survival; cancer growth; nonhuman; disease free survival; cancer staging; dna polymerase; cell proliferation; prostate specific antigen; cell viability; cell survival; cell cycle progression; dna repair; progression free survival; gene expression; tumor volume; small interfering rna; rna interference; tumor xenograft; enzyme activity; enzyme linked immunosorbent assay; radiation exposure; radiation response; carcinogenesis; prostate cancer; ubiquitination; genetic transfection; microarray analysis; western blotting; growth regulation; immunoblotting; reporter gene; cell cycle checkpoint; radiosensitivity; binding site; crystal structure; upregulation; oxidative stress; bone marrow cell; tumor growth; mtor signaling; protein microarray; radiosensitization; pharmacology; rna sequence; small cell lung cancer; chloroquine; growth inhibition; radiation tolerance; transcription factor ezh2; colony formation; epithelial mesenchymal transition; atomic force microscopy; autophagosome; cancer prognosis; autophagic cell death; dna end joining repair; berberine; human; article; luciferase assay; droplet digital polymerase chain reaction; ampk signaling; autophagy (cellular); dna directed dna polymerase theta |
| Journal Title: | Cancer Letters |
| Volume: | 597 |
| ISSN: | 0304-3835 |
| Publisher: | Elsevier Ireland Ltd. |
| Date Published: | 2024-08-10 |
| Start Page: | 217063 |
| Language: | English |
| DOI: | 10.1016/j.canlet.2024.217063 |
| PUBMED: | 38925361 |
| PROVIDER: | scopus |
| PMCID: | PMC12175492 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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