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Guanylate-binding protein 1 modulates proteasomal machinery in ovarian cancer

Dhanir Tailor1,2, Fernando Jose Garcia-Marques3, Abel Bermudez3

  • 1Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.

Iscience
|November 29, 2023
PubMed

Insights

Guanylate-binding protein 1 (GBP1) inhibition limits ovarian cancer cell growth and enhances chemotherapy response by reducing proteasomal activity. GBP1 overexpression promotes tumor progression and chemoresistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Guanylate-binding protein 1 (GBP1) is an interferon-γ-induced GTPase.
  • Its role in ovarian cancer (OC) progression and chemoresistance is not fully understood.

Purpose of the Study:

  • To investigate the function of GBP1 in ovarian cancer.
  • To elucidate the molecular mechanisms underlying GBP1's role in tumor progression and chemosensitivity.

Main Methods:

  • Genetically modified ovarian cancer cell lines with altered GBP1 expression (knockdown and overexpression).
  • In vivo tumor xenograft models.
  • Proteomics-based thermal stability assay (CETSA).
  • Assessment of proteasomal activity and ubiquitinated protein levels.

Main Results:

  • GBP1 inhibition reduced cancer cell clonogenic potential and delayed tumor progression in vivo.
  • GBP1 overexpression promoted tumor progression and reduced median survival.
  • CETSA revealed GBP1 interacts with proteasome components.
  • GBP1 inhibition sensitized OC cells to paclitaxel by decreasing proteasomal activity and increasing ubiquitinated proteins.
  • GBP1 overexpression conferred paclitaxel resistance via enhanced proteasomal activity.

Conclusions:

  • GBP1 plays a critical role in ovarian cancer progression and chemoresistance.
  • GBP1 modulates proteasomal activity, influencing cellular response to chemotherapy.
  • Targeting GBP1 may represent a therapeutic strategy to overcome paclitaxel resistance in ovarian cancer.
Keywords:
BiochemistryCancerMolecular biologyPharmacologyProteomics

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