Fluorizoline Blocks the Interaction between Prohibitin-2 and γ-Glutamylcyclotransferase and Induces p21Waf1/Cip1 Expression in MCF7 Breast Cancer Cells
Fluorizoline Blocks the Interaction between Prohibitin-2 and γ-Glutamylcyclotransferase and Induces p21Waf1/Cip1 Expression in MCF7 Breast Cancer Cells
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DOI：
10.1124/molpharm.121.000334
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发表时间：
2022-02-01
影响因子：
3.6
通讯作者：
Nakata, Susumu
中科院分区：
文献类型：
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作者：
Takagi, Hiroko;Moyama, Chiami;Nakata, Susumu
prohibition -2 （PHB2）是一种具有多种功能的支架蛋白，其功能包括与细胞质中的c-谷氨酰环转移酶（GGCT）相互作用以及抑制细胞核中p21Waf1/Cip （p21）基因的转录活性。细胞毒性药物氟唑啉与PHB1/2结合，对癌细胞发挥抗增殖作用。然而，氟唑啉抗增殖作用的确切机制尚未完全阐明。在本研究中，我们首次发现氟唑啉在包括MCF7乳腺癌细胞在内的几种人类癌细胞系中诱导p21表达。氟唑啉处理MCF7细胞可抑制细胞增殖，阻止细胞进入DNA合成期。p21的敲低恢复了被抑制的增殖，表明氟唑啉通过诱导p21抑制MCF7细胞的生长。MCF7细胞中过表达PHB2可阻止氟唑啉诱导p21的表达，恢复其抗增殖作用和阻断细胞周期进程。此外，氟唑啉处理MCF7细胞抑制了内源性PHB2和GGCT蛋白的相互作用，降低了PHB2蛋白的核定位水平。这些结果表明，用氟唑啉靶向PHB2可诱导p21的表达，从而抑制癌细胞的增殖。意义声明本研究表明氟唑啉可能是一种有前景的新型抗癌候选药物，它可以诱导p21的表达并阻断人类癌细胞的细胞周期进程。此外，我们发现氟唑啉抑制了PHB2和GGCT之间的相互作用，降低了PHB2蛋白的核定位。
Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with c-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 STATEMENTThis 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.