| RRC ID |
78765
|
| 著者 |
Masuo H, Kubota K, Shimizu A, Notake T, Miyazaki S, Yoshizawa T, Sakai H, Hayashi H, Soejima Y.
|
| タイトル |
Increased mitochondria are responsible for the acquisition of gemcitabine resistance in pancreatic cancer cell lines.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
Pancreatic ductal adenocarcinoma has a particularly poor prognosis as it is often detected at an advanced stage and acquires resistance to chemotherapy early during its course. Stress adaptations by mitochondria, such as metabolic plasticity and regulation of apoptosis, promote cancer cell survival; however, the relationship between mitochondrial dynamics and chemoresistance in pancreatic ductal adenocarcinoma remains unclear. We here established human pancreatic cancer cell lines resistant to gemcitabine from MIA PaCa-2 and Panc1 cells. We compared the cells before and after the acquisition of gemcitabine resistance to investigate the mitochondrial dynamics and protein expression that contribute to this resistance. The mitochondrial number increased in gemcitabine-resistant cells after resistance acquisition, accompanied by a decrease in mitochondrial fission 1 protein, which induces peripheral mitosis, leading to mitophagy. An increase in the number of mitochondria promoted oxidative phosphorylation and increased anti-apoptotic protein expression. Additionally, enhanced oxidative phosphorylation decreased the AMP/ATP ratio and suppressed AMPK activity, resulting in the activation of the HSF1-heat shock protein pathway, which is required for environmental stress tolerance. Synergistic effects observed with BCL2 family or HSF1 inhibition in combination with gemcitabine suggested that the upregulated expression of apoptosis-related proteins caused by the mitochondrial increase may contribute to gemcitabine resistance. The combination of gemcitabine with BCL2 or HSF1 inhibitors may represent a new therapeutic strategy for the treatment of acquired gemcitabine resistance in pancreatic ductal adenocarcinoma.
|
| 巻・号 |
114(11)
|
| ページ |
4388-4400
|
| 公開日 |
2023-11-1
|
| DOI |
10.1111/cas.15962
|
| PMID |
37700464
|
| PMC |
PMC10637055
|
| MeSH |
Apoptosis
Apoptosis Regulatory Proteins / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Drug Resistance, Neoplasm
Gemcitabine
Humans
Mitochondria / metabolism
Pancreatic Neoplasms* / pathology
Proto-Oncogene Proteins c-bcl-2 / metabolism
|
| リソース情報 |
| ヒト・動物細胞 |
PANC-1(RCB2095)
PK-59(RCB1901) |
