Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth

Abstract

Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.

SFI1 promotes centriole duplication by recruiting USP9X to stabilize the microcephaly protein STIL

“…Reduced USP9X expression confers selective growth advantage to various tumors (Schwickart et al, 2010; Pérez-Mancera et al, 2012; Peng et al, 2013; Kushwaha et al, 2015; Yang et al, 2016; Zhang et al, 2016; Toloczko et al, 2017; Khan et al, 2018; Li et al, 2018; Pal et al, 2018). Therefore, we investigated the stability of additional USP9X targets in MRXS99F fibroblasts.…”

Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid

“…The function of USP9x is cell-type specific. USP9x has been viewed as a tumor suppressor gene in colorectal and pancreatic ductal adenocarcinoma, while others reported that USP9x is an oncogene in breast cancer, glioblastoma, and leukemia (Akiyama et al, 2019;Chen et al, 2019;Khan et al, 2018a;Pal et al, 2018;Potu et al, 2017b;Zhu et al, 2018). Our results suggest that USP9x may function as an not certified by peer review) is the author/funder.…”

<p>MiR-223-3p targeting epithelial cell transforming sequence 2 oncogene inhibits the activity, apoptosis, invasion and migration of MDA-MB-468 breast cancer cells</p>

“…The significant downregulation of ECT2 expression in the miR-223-3p mimic group further confirmed that miR-223-3p could regulate the expression of ECT2. The biological behavior of cancer cells is an important marker reflecting the progress and severity of cancer 28–30. In order to explore how miR-223-3p and ECT2 are involved in the regulation of biological characteristics of BC cells, CCK8 and flow cytometry were used to detect the cell viability and apoptosis in each group.…”