Guanylate-binding protein 1 modulates proteasomal machinery in ovarian cancer

Dhanir Tailor; Fernando Jose Garcia-Marques; Abel Bermudez; Sharon J Pitteri; Sanjay V Malhotra

doi:10.1016/j.isci.2023.108292

Guanylate-binding protein 1 modulates proteasomal machinery in ovarian cancer

iScience. 2023 Oct 24;26(11):108292. doi: 10.1016/j.isci.2023.108292. eCollection 2023 Nov 17.

Authors

Dhanir Tailor^{1

2}, Fernando Jose Garcia-Marques³, Abel Bermudez³, Sharon J Pitteri³, Sanjay V Malhotra^{1

2}

Affiliations

¹ Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.
² Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA.
³ Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA 94304, USA.

Abstract

Guanylate-binding protein 1 (GBP1) is known as an interferon-γ-induced GTPase. Here, we used genetically modified ovarian cancer (OC) cells to study the role of GBP1. The data generated show that GBP1 inhibition constrains the clonogenic potential of cancer cells. In vivo studies revealed that GBP1 overexpression in tumors promotes tumor progression and reduces median survival, whereas GBP1 inhibition delayed tumor progression with longer median survival. We employed proteomics-based thermal stability assay (CETSA) on GBP1 knockdown and overexpressed OC cells to study its molecular functions. CETSA results show that GBP1 interacts with many members of the proteasome. Furthermore, GBP1 inhibition sensitizes OC cells to paclitaxel treatment via accumulated ubiquitinylated proteins where GBP1 inhibition decreases the overall proteasomal activity. In contrast, GBP1-overexpressing cells acquired paclitaxel resistance via boosted cellular proteasomal activity. Overall, these studies expand the role of GBP1 in the activation of proteasomal machinery to acquire chemoresistance.

Keywords: Biochemistry; Cancer; Molecular biology; Pharmacology; Proteomics.