The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells
ABSTRACTThe antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential invo...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2024.2302413 |
| _version_ | 1797306808612683776 |
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| author | Ge Jiang Xingzhi Zhou Ye Hu Xiaoyu Tan Dan Wang Lina Yang Qinggao Zhang Shuangping Liu |
| author_facet | Ge Jiang Xingzhi Zhou Ye Hu Xiaoyu Tan Dan Wang Lina Yang Qinggao Zhang Shuangping Liu |
| author_sort | Ge Jiang |
| collection | DOAJ |
| description | ABSTRACTThe antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment. |
| first_indexed | 2024-03-08T00:47:11Z |
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| id | doaj.art-81351c06bc5b48f8be355d1a36c2d5f8 |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-08T00:47:11Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-81351c06bc5b48f8be355d1a36c2d5f82024-02-15T07:15:17ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762024-12-0125110.1080/15384047.2024.2302413The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cellsGe Jiang0Xingzhi Zhou1Ye Hu2Xiaoyu Tan3Dan Wang4Lina Yang5Qinggao Zhang6Shuangping Liu7Chronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaDepartment of Clinical Laboratory, Xin Hua Hospital Affiliated to Dalian University, Dalian, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaChronic Disease Research Center, Medical College, Dalian University, Dalian, Liaoning, ChinaABSTRACTThe antipsychotic drug pimozide has been demonstrated to inhibit cancer. However, the precise anti-cancer mechanism of pimozide remains unclear. The purpose of this study was to investigate the effects of pimozide on human MCF-7 and MDA-MB-231 breast cancer cell lines, and the potential involvement in the RAF/ERK signaling. The effects of pimozide on cells were examined by 4,5-dimethylthiazol-2-yl-3,5-diphenylformazan, wound healing, colony formation, transwell assays, and caspase activity assay. Flow cytometry and acridine orange and ethidium bromide staining were performed to assess changes in cells. Transmission electron microscopy and monodansylcadaverine staining were used to observe autophagosomes. The cyclic adenosine monophosphate was evaluated using the FRET system. Immunohistochemistry, immunofluorescence, RNA interference, and western blot investigated the expression of proteins. Mechanistically, we focus on the RAF1/ERK signaling. We detected pimozide was docked to RAF1 by Schrodinger software. Pimozide down-regulated the phosphorylation of RAF1, ERK 1/2, Bcl-2, and Bcl-xl, up-regulated Bax, and cleaved caspase-9 to induce apoptosis. Pimozide might promote autophagy by up-regulating cAMP. The enhancement of autophagy increased the conversion of LC3-I to LC3-II and down-regulated p62 expression. But mTOR signaling was not involved in promoting autophagy. The knockdown of RAF1 expression induced autophagy and apoptosis in breast cancer cells, consistent with the results of pimozide or sorafenib alone. Blocked autophagy by chloroquine resulted in the impairment of pimozide-induced apoptosis. These data showed that pimozide inhibits breast cancer by regulating the RAF/ERK signaling pathway and might activate cAMP-induced autophagy to promote apoptosis and it may be a potential drug for breast cancer treatment.https://www.tandfonline.com/doi/10.1080/15384047.2024.2302413Breast cancerPimozideRAF/ERKApoptosisAutophagy |
| spellingShingle | Ge Jiang Xingzhi Zhou Ye Hu Xiaoyu Tan Dan Wang Lina Yang Qinggao Zhang Shuangping Liu The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells Cancer Biology & Therapy Breast cancer Pimozide RAF/ERK Apoptosis Autophagy |
| title | The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells |
| title_full | The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells |
| title_fullStr | The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells |
| title_full_unstemmed | The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells |
| title_short | The antipsychotic drug pimozide promotes apoptosis through the RAF/ERK pathway and enhances autophagy in breast cancer cells |
| title_sort | antipsychotic drug pimozide promotes apoptosis through the raf erk pathway and enhances autophagy in breast cancer cells |
| topic | Breast cancer Pimozide RAF/ERK Apoptosis Autophagy |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2024.2302413 |
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