Fluorizolin blocks the interaction between prohibitin-2 and gamma-glutamylcyclotransferase and induces p21 (Waf1 / Cip1) expression in MCF7 breast cancer cells

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Mol Pharmacol. December 3, 2021: MOLPHARM-AR-2021-000334. doi: 10.1124 / molpharm.121.000334. Online ahead of print.

ABSTRACT

Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include the interaction with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and the repression of transcriptional activities of the cytoplasm. p21Waf1 / Cip (p21) gene in the nucleus. The cytotoxic drug fluorizolin binds to PHB1 / 2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizolin is not fully understood. In the present study, we first show that fluorizolin induces the expression of p21 in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizolin suppressed proliferation and prevented cells from entering the DNA synthesis phase. Reversal of p21 rescued suppressed proliferation, indicating that fluorizolin inhibited the growth of MCF7 cells via induction of p21. Overexpression of PHB2 in MCF7 cells prevented induction of p21 expression by fluorizoline and restored antiproliferative effects and blockade of cell cycle progression. In addition, treatment of MCF7 cells with fluorizolin inhibited the interaction between endogenous PHB2 and GGCT proteins and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting of PHB2 with fluorizolin induces expression of p21 and therefore blocks the proliferation of cancer cells. Statement of significance This study shows that fluorizoline may be a promising new cancer drug candidate that induces p21 expression and blocks cell cycle progression in human cancer cell lines. In addition, we show that fluorizolin inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of the PHB2 proteins that regulate the expression of p21.

PMID: 34862308 | DOI: 10.1124 / molpharm.121.000334


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Shawn Beecher

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