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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1547164

Small molecule inhibition of ubiquitin C-terminal hydrolase L1 alters cell metabolism proteins and exerts anti-or pro-tumorigenic effects contingent upon chemosensitivity status in high grade serous ovarian cancer

Provisionally accepted
Corinne Jansen Corinne Jansen 1,2Julia Mcadams Julia Mcadams 1Chloe Kim Chloe Kim 3Payton De La Cruz Payton De La Cruz 1Angelica Salaverria Angelica Salaverria 4Nicholas DaSilva Nicholas DaSilva 5Kathryn Grive Kathryn Grive 1,2Nicole James Nicole James 1,2*
  • 1 Women & Infants Hospital of Rhode Island, Providence, Rhode Island, United States
  • 2 Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States
  • 3 School of Public Health, Brown University, Providence, Rhode Island, United States
  • 4 Therapeutic Sciences Graduate Program, Brown University, Providence, Rhode Island, United States
  • 5 Division of Biology and Medicine, Proteomics Facility, Brown University,, Providence, United States

The final, formatted version of the article will be published soon.

    High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies in which the majority of patients eventually develop chemoreistant recurrent disease. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme canonically known for its involvement in neurodegeneration, but recently has been shown to play a key role in tumorigenesis. Furthermore, UCHL1 has garnered attention across a multitude of cancer subtypes as it has the ability to be targeted through small molecule inhibition. Therefore, the goal of this present study was to elucidate mechanistic consequences of small molecule UCHL1 inhibition in HGSOC. Comparative label-free proteomic analysis of HGSOC cell line, OVCAR8 revealed prominent changes in cell metabolism proteins upon treatment with UCHL1 small molecule inhibitor, LDN-5744. Further validation via western blot analysis revealed that changes in cell metabolism proteins differed in matched chemo-sensitive versus -resistant HGSOC cells. Finally, cell viability analysis demonstrated that a combinatorial carboplatin and LDN-5744 blockade produced a promotion or conversely, inhibition of cell death , in chemoresistant, and chemosensitve HGSOC cells, respectively. This phenomenon was further corroborated by respective differences in activation levels of common tumor cell growth pathways STAT3, MAPK/ERK, and AKT in chemoresistant versus chemosensitve HGSOC cells. Overall, this investigation established that pharmacologic targeting of UCHL1 produces differential effects according to HGSOC chemosensitivity status.

    Keywords: High grade serous ovarian cancer (HGSOC), chemoresisitance, chemosensitivity, LDN-5744, Uchl1

    Received: 17 Dec 2024; Accepted: 03 Feb 2025.

    Copyright: © 2025 Jansen, Mcadams, Kim, De La Cruz, Salaverria, DaSilva, Grive and James. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Nicole James, Women & Infants Hospital of Rhode Island, Providence, RI 02905, Rhode Island, United States

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