| RRC ID |
71953
|
| 著者 |
Takagi H, Moyama C, Taniguchi K, Ando K, Matsuda R, Ando S, Ii H, Kageyama S, Kawauchi A, Chouha N, Désaubry L, Nakata S.
|
| タイトル |
Fluorizoline Blocks the Interaction between Prohibitin-2 and γ-Glutamylcyclotransferase and Induces p21Waf1/Cip1 Expression in MCF7 Breast Cancer Cells.
|
| ジャーナル |
Mol Pharmacol
|
| Abstract |
Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21Waf1/Cip (p21) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into the DNA synthesis phase. Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells. SIGNIFICANCE STATEMENT: This study shows that fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins.
|
| 巻・号 |
101(2)
|
| ページ |
78-86
|
| 公開日 |
2022-2-1
|
| DOI |
10.1124/molpharm.121.000334
|
| PII |
molpharm.121.000334
|
| PMID |
34862308
|
| MeSH |
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Cell Proliferation / drug effects
Cell Proliferation / physiology
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / physiology*
Humans
MCF-7 Cells
Prohibitins / antagonists & inhibitors
Prohibitins / metabolism*
gamma-Glutamylcyclotransferase / antagonists & inhibitors
gamma-Glutamylcyclotransferase / metabolism*
|
| IF |
3.664
|
| リソース情報 |
| ヒト・動物細胞 |
PC-3(RCB2145) |
