Reference - Detail
| RRC ID | 77177 |
|---|---|
| Author | Amada K, Hijiya N, Ikarimoto S, Yanagihara K, Hanada T, Hidano S, Kurogi S, Tsukamoto Y, Nakada C, Kinoshita K, Hirashita Y, Uchida T, Shin T, Yada K, Hirashita T, Kobayashi T, Murakami K, Inomata M, Shirao K, Aoki M, Takekawa M, Moriyama M. |
| Title | Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor. |
| Journal | Cancer Sci |
| Abstract |
Constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway is essential for tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). To date, however, almost all clinical trials of inhibitor targeting this pathway have failed to improve the outcome of patients with PDAC. We found that implanted MIA Paca2, a human PDAC cell line sensitive to a MAPK inhibitor, PD0325901, became refractory within a week after treatment. By comparing the expression profiles of MIA Paca2 before and after acquisition of the refractoriness to PD0325901, we identified clusterin (CLU) as a candidate gene involved. CLU was shown to be induced immediately after treatment with PD0325901 or expressed primarily in more than half of PDAC cell lines, enhancing cell viability by escaping from apoptosis. A combination of PD0325901 and CLU downregulation was found to synergistically or additively reduce the proliferation of PDAC cells. In surgically resected PDAC tissues, overexpression of CLU in cancer cells was observed immunohistochemically in approximately half of the cases studied. Collectively, our findings highlight the mechanisms responsible for the rapid refractory response to MEK inhibitor in PDAC cells, suggesting a novel therapeutic strategy that could be applicable to patients with PDAC using inhibitor targeting the MAPK signaling pathway and CLU. |
| Volume | 114(5) |
| Pages | 2189-2202 |
| Published | 2023-5-1 |
| DOI | 10.1111/cas.15735 |
| PMID | 36694355 |
| PMC | PMC10154874 |
| MeSH | Carcinoma, Pancreatic Ductal* / drug therapy Carcinoma, Pancreatic Ductal* / genetics Carcinoma, Pancreatic Ductal* / metabolism Cell Line, Tumor Cell Proliferation Clusterin / genetics Clusterin / metabolism Clusterin / therapeutic use Humans Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / genetics Pancreatic Neoplasms* / metabolism Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use |
| IF | 4.966 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | PK-45H(RCB1973) PK-59(RCB1901) MIA Paca2(RCB2094) PANC-1(RCB2095) PK-1(RCB972) |