| RRC ID |
76426
|
| 著者 |
Pan YR, Wu CE, Jung SM, Huang SC, Lin SH, Chou WC, Chang YC, Chen MH, Hung TH, Yu AL, Huang WK, Yeh CN.
|
| タイトル |
Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.
|
| ジャーナル |
Int J Biol Sci
|
| Abstract |
Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.
|
| 巻・号 |
19(9)
|
| ページ |
2772-2786
|
| 公開日 |
2023-1-1
|
| DOI |
10.7150/ijbs.79126
|
| PII |
ijbsv19p2772
|
| PMID |
37324940
|
| PMC |
PMC10266071
|
| MeSH |
Afatinib / therapeutic use
Bile Duct Neoplasms* / pathology
Bile Ducts, Intrahepatic / metabolism
Cell Line, Tumor
Cholangiocarcinoma* / metabolism
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Drug Resistance, Neoplasm / genetics
ErbB Receptors
Gemcitabine
Humans
Mucin-4 / genetics
Pancreatic Neoplasms* / pathology
Proto-Oncogene Proteins c-akt
|
| IF |
4.858
|
| リソース情報 |
| ヒト・動物細胞 |
SSP-25(RCB1293) |
