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RNA-binding protein HuR inhibition induces multiple programmed cell death in breast and prostate cancer.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : BioMed Central, c2003-
    • Subject Terms:
      Prostatic Neoplasms*/pathology ; Prostatic Neoplasms*/metabolism ; Prostatic Neoplasms*/genetics ; ELAV-Like Protein 1*/metabolism ; ELAV-Like Protein 1*/genetics ; Breast Neoplasms*/pathology ; Breast Neoplasms*/metabolism ; Breast Neoplasms*/genetics ; Apoptosis*/drug effects; Humans ; Male ; Animals ; Cell Line, Tumor ; Mice ; Female ; Cell Proliferation/drug effects ; Ferroptosis/drug effects ; Mice, Nude
    • Abstract:
      The RNA-binding protein Hu antigen R (HuR) plays a pivotal role in cancer progression, and previous studies have demonstrated its involvement in suppressing cell death in cancer. However, the precise mechanisms underlying HuR inhibition-induced cell death remain elusive. Here, we investigated the impacts of HuR functional inhibition via the small molecule inhibitor KH-3 on cell proliferation, colony formation, and cell death across multiple cancer cell lines, with an emphasis on breast and prostate cancers. KH-3 treatment induced apoptotic cell death of various cancer cell lines, as well as autophagy-associated cell death and ferroptosis. Remarkably, KH-3-induced cell death was partially rescued by an autophagy inhibitor and a ferroptosis inhibitor. The anti-tumor effects of KH-3 were further validated in two mouse xenograft models of human prostate cancer. Mechanistically, KH-3 reduced the expression of HuR targets involved in apoptosis and ferroptosis suppression, including cFLIP and SLC7A11, respectively. Moreover, cFLIP silencing enhanced Caspase-8 activation as well as PARP cleavage in both breast cancer and prostate cancer cells. Both KH-3-induced pharmacological HuR inhibition and RNA interference-mediated HuR knockdown reduced the expression of SLC7A11. Additionally, KH-3 also reduced XIAP and Survivin, enhancing the activation of multiple caspases and leading to apoptosis. This study highlights the critical roles of HuR in programmed cell death regulation, advocating HuR inhibition as a promising anti-tumor strategy for cell-death-inducing cancer therapy.
      Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
      (© 2024. The Author(s).)
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    • Contributed Indexing:
      Keywords: Breast cancer; Cell death; HuR; Mouse tumor models; Prostate cancer
    • Accession Number:
      0 (ELAV-Like Protein 1)
      0 (ELAVL1 protein, human)
    • Publication Date:
      Date Created: 20241203 Date Completed: 20241204 Latest Revision: 20241207
    • Publication Date:
      20241209
    • Accession Number:
      PMC11613925
    • Accession Number:
      10.1186/s12964-024-01916-z
    • Accession Number:
      39627778