RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth
Recommended Citation
Bannoura SF, Aboukameel A, Yar Khan H, Uddin MH, Jang H, Beal E, Thangasamy A, Shi Y, Kim S, Wagner KU, Beydoun R, El-Rayes BF, Philip PA, Mohammad RM, Saif MW, Al-Hallak MN, Pasche BC, and Azmi AS. RCC1 regulation of subcellular protein localization via Ran GTPase drives pancreatic ductal adenocarcinoma growth. Cancer Lett 2024; 217275.
Document Type
Article
Publication Date
11-1-2024
Publication Title
Cancer letters
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with limited therapeutic options. Here, we evaluated the role of regulator of chromosome condensation 1 (RCC1) in PDAC. RCC1 functions as a guanine exchange factor for GTP-binding nuclear protein Ran (Ran) GTPase and is involved in nuclear cytoplasmic transport. RCC1 RNA expression is elevated in PDAC tissues compared to normal pancreatic tissues and correlates with poor prognosis. RCC1 silencing by RNAi and CRISPR-Cas9 knockout (KO) results in reduced proliferation in 2-D and 3-D cell cultures. RCC1 KD reduced migration and clonogenicity, enhanced apoptosis, and altered cell cycle progression in human PDAC and murine cells from LSL-Kras(G12D/+); LSL-Trp53(R172H/+); Pdx1-Cre (KPC) tumors. Mechanistically, RCC1 KO shows widespread transcriptomic alterations including regulation of PTK7, a co-receptor of the Wnt signaling pathway. RCC1 KD disrupted subcellular Ran localization and the Ran gradient. Nuclear and cytosolic proteomics revealed altered subcellular proteome localization in Rcc1 KD KPC-tumor-derived cells, and the alteration of several metabolic biosynthesis pathways. In vivo, RCC1 KO cells show reduced tumor growth potential when injected as sub-cutaneous xenografts. Finally, RCC1 knockdown sensitized PDAC cells to gemcitabine chemotherapy treatment. This study reveals the role of RCC1 in pancreatic cancer as a novel molecular vulnerability that could be exploited to enhance therapeutic response.
Medical Subject Headings
Humans; Carcinoma, Pancreatic Ductal; ran GTP-Binding Protein; Pancreatic Neoplasms; Animals; Mice; Cell Line, Tumor; Cell Proliferation; Guanine Nucleotide Exchange Factors; Cell Cycle Proteins; Deoxycytidine; Gemcitabine; Gene Expression Regulation, Neoplastic; Nuclear Proteins; Cell Movement; Apoptosis
PubMed ID
39321913
ePublication
ePub ahead of print
Volume
604
First Page
217275
Last Page
217275
