Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma
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Published:2024-04-05
Issue:7
Volume:25
Page:4056
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Fujiwara-Tani Rina1, Sasaki Takamitsu1, Bhawal Ujjal Kumar2ORCID, Mori Shiori1, Ogata Ruiko1, Sasaki Rika1, Ikemoto Ayaka1, Kishi Shingo13, Fujii Kiyomu1, Ohmori Hitoshi1, Sho Masayuki4, Kuniyasu Hiroki1ORCID
Affiliation:
1. Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan 2. Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo 271-8587, Chiba, Japan 3. Pathology Laboratory, Research Institute, Tokushukai Nozaki Hospital, 2-10-50 Tanigawa, Daito 574-0074, Osaka, Japan 4. Department of Surgery, Nara Medical University, Kashihara 634-8522, Nara, Japan
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with a 5-year survival rate of less than 10%. Furthermore, the acquisition of anticancer drug resistance makes PDAC treatment difficult. We established MIA-GEM cells, a PDAC cell line resistant to gemcitabine (GEM), a first-line anticancer drug, using the human PDAC cell line—MIA-PaCa-2. Microtubule-associated serine/threonine kinase-4 (MAST4) expression was increased in MIA-GEM cells compared with the parent cell line. Through inhibitor screening, dysregulated AKT signaling was identified in MIA-GEM cells with overexpression of AKT3. MAST4 knockdown effectively suppressed AKT3 overexpression, and both MAST4 and AKT3 translocation into the nucleus, phosphorylating forkhead box O3a (FOXO3) in MIA-GEM cells. Modulating FOXO3 target gene expression in these cells inhibited apoptosis while promoting stemness and proliferation. Notably, nuclear MAST4 demonstrated higher expression in GEM-resistant PDAC cases compared with that in the GEM-sensitive cases. Elevated MAST4 expression correlated with a poorer prognosis in PDAC. Consequently, nuclear MAST4 emerges as a potential marker for GEM resistance and poor prognosis, representing a novel therapeutic target for PDAC.
Funder
MEXT KAKENHI Ministry of Education, Culture, Sports, Science, and Technology, Japan
Reference54 articles.
1. Higashi, T., Ishii, T., Katanoda, K., Fujishita, M., and Matsuda, T. (2013). Cancer Statistics in Japan, 2023, Foundation for Promotion of Cancer Research. 2. Howlander, N., Noone, A., and Krapcho, M. (2023, November 07). SEER Cancer Statistics Review, 1975–2017, Available online: https://seer.cancer.gov/csr/1975_2017/. 3. Pancreatic cancer;Kleeff;Nat. Rev. Dis. Primers,2016 4. Pancreatic Cancer: A Review;Park;JAMA,2021 5. Pancreatic cancer;Mizrahi;Lancet,2020
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