Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells
We recently demonstrated that the histone deacetylase inhibitor valproic acid (VPA) reprograms the cisplatin-induced metabolome of triple-negative breast cancer (TNBC) cells, including a shift in hexose levels. Accordingly, here, we tested the hypothesis that VPA alters glucose metabolism in correla...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1217149/full |
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| author | Avital Granit Mizrahi Avital Granit Mizrahi Ahinoam Gugenheim Haneen Hamad Roa’a Hamed Nino Tetro Ofra Maimon Salome Khutsurauli Hovav Nechushtan Benjamin Nisman Deborah Duran Deborah Duran Widad Samman Widad Samman Liron Birimberg-Schwartz Liron Birimberg-Schwartz Liron Birimberg-Schwartz Myriam Grunewald Myriam Grunewald Sara Eyal Tamar Peretz Tamar Peretz |
| author_facet | Avital Granit Mizrahi Avital Granit Mizrahi Ahinoam Gugenheim Haneen Hamad Roa’a Hamed Nino Tetro Ofra Maimon Salome Khutsurauli Hovav Nechushtan Benjamin Nisman Deborah Duran Deborah Duran Widad Samman Widad Samman Liron Birimberg-Schwartz Liron Birimberg-Schwartz Liron Birimberg-Schwartz Myriam Grunewald Myriam Grunewald Sara Eyal Tamar Peretz Tamar Peretz |
| author_sort | Avital Granit Mizrahi |
| collection | DOAJ |
| description | We recently demonstrated that the histone deacetylase inhibitor valproic acid (VPA) reprograms the cisplatin-induced metabolome of triple-negative breast cancer (TNBC) cells, including a shift in hexose levels. Accordingly, here, we tested the hypothesis that VPA alters glucose metabolism in correlation with cisplatin sensitivity. Two TNBC cell lines, MDA-MB-231 (a cisplatin-resistant line) and MDA-MB-436 (a cisplatin-sensitive line), were analyzed. The glycolysis and oxidative metabolism were measured using the Glycolysis Stress Test kit. The expression of aldehyde dehydrogenases (ALDHs), enzymes linked to drug resistance, was investigated by Western blot and real-time PCR analyses. We additionally studied the influence of ALDH inhibition by disulfiram on the viability of MDA-MB-231 cells and on a TNBC patient-derived organoid system. Cisplatin treatment reduced the extracellular acidification rate in MDA-MB-436 cells but not MDA-MB-231 cells, whereas VPA addition increased the extracellular acidification rate in both cell lines. VPA further reduced the oxygen consumption rate of cisplatin-treated MDA-MB-436 cells, which correlated with cell cycle alterations. However, in MDA-MB-231 cells, the cell cycle distribution did not change between cisplatin/VPA–cisplatin treatments. In both cell lines, VPA increased the expression of ALDH isoform and ALDH1A1 expression. However, only in MDA-MB-231 cells, VPA synergized with cisplatin to augment this effect. Disulfiram sensitized the cells to the cytotoxic effects of the VPA–cisplatin combination. Furthermore, the disulfiram–VPA–chemotherapy combination was most effective in TNBC organoids. Our results show that ALDH overexpression may act as one mechanism of cellular resistance to VPA in TNBC and that its inhibition may enhance the therapeutic efficacy of VPA–chemotherapeutic drug combinations. |
| first_indexed | 2024-03-11T15:35:02Z |
| format | Article |
| id | doaj.art-5c2f7c8cf790418bbeab010b21580f0d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-11T15:35:02Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-5c2f7c8cf790418bbeab010b21580f0d2023-10-26T22:43:44ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-10-011110.3389/fcell.2023.12171491217149Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cellsAvital Granit Mizrahi0Avital Granit Mizrahi1Ahinoam Gugenheim2Haneen Hamad3Roa’a Hamed4Nino Tetro5Ofra Maimon6Salome Khutsurauli7Hovav Nechushtan8Benjamin Nisman9Deborah Duran10Deborah Duran11Widad Samman12Widad Samman13Liron Birimberg-Schwartz14Liron Birimberg-Schwartz15Liron Birimberg-Schwartz16Myriam Grunewald17Myriam Grunewald18Sara Eyal19Tamar Peretz20Tamar Peretz21Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelSchool of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelSchool of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, IsraelSchool of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelFaculty of Medicine, Hebrew University, Jerusalem, IsraelHadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, IsraelFaculty of Medicine, Hebrew University, Jerusalem, IsraelHadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, IsraelFaculty of Medicine, Hebrew University, Jerusalem, IsraelHadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, IsraelDepartment of Pediatric Gastroenterology, The Hadassah Medical Organization, Jerusalem, IsraelFaculty of Medicine, Hebrew University, Jerusalem, IsraelHadassah Organoid Center, The Hadassah Medical Organization, Jerusalem, IsraelSchool of Pharmacy, Institute for Drug Research, The Hebrew University, Jerusalem, IsraelOncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, IsraelFaculty of Medicine, Hebrew University, Jerusalem, IsraelWe recently demonstrated that the histone deacetylase inhibitor valproic acid (VPA) reprograms the cisplatin-induced metabolome of triple-negative breast cancer (TNBC) cells, including a shift in hexose levels. Accordingly, here, we tested the hypothesis that VPA alters glucose metabolism in correlation with cisplatin sensitivity. Two TNBC cell lines, MDA-MB-231 (a cisplatin-resistant line) and MDA-MB-436 (a cisplatin-sensitive line), were analyzed. The glycolysis and oxidative metabolism were measured using the Glycolysis Stress Test kit. The expression of aldehyde dehydrogenases (ALDHs), enzymes linked to drug resistance, was investigated by Western blot and real-time PCR analyses. We additionally studied the influence of ALDH inhibition by disulfiram on the viability of MDA-MB-231 cells and on a TNBC patient-derived organoid system. Cisplatin treatment reduced the extracellular acidification rate in MDA-MB-436 cells but not MDA-MB-231 cells, whereas VPA addition increased the extracellular acidification rate in both cell lines. VPA further reduced the oxygen consumption rate of cisplatin-treated MDA-MB-436 cells, which correlated with cell cycle alterations. However, in MDA-MB-231 cells, the cell cycle distribution did not change between cisplatin/VPA–cisplatin treatments. In both cell lines, VPA increased the expression of ALDH isoform and ALDH1A1 expression. However, only in MDA-MB-231 cells, VPA synergized with cisplatin to augment this effect. Disulfiram sensitized the cells to the cytotoxic effects of the VPA–cisplatin combination. Furthermore, the disulfiram–VPA–chemotherapy combination was most effective in TNBC organoids. Our results show that ALDH overexpression may act as one mechanism of cellular resistance to VPA in TNBC and that its inhibition may enhance the therapeutic efficacy of VPA–chemotherapeutic drug combinations.https://www.frontiersin.org/articles/10.3389/fcell.2023.1217149/fullvalproic acidcisplatindisulfiramglucosemetabolismaldehyde dehydrogenase |
| spellingShingle | Avital Granit Mizrahi Avital Granit Mizrahi Ahinoam Gugenheim Haneen Hamad Roa’a Hamed Nino Tetro Ofra Maimon Salome Khutsurauli Hovav Nechushtan Benjamin Nisman Deborah Duran Deborah Duran Widad Samman Widad Samman Liron Birimberg-Schwartz Liron Birimberg-Schwartz Liron Birimberg-Schwartz Myriam Grunewald Myriam Grunewald Sara Eyal Tamar Peretz Tamar Peretz Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells Frontiers in Cell and Developmental Biology valproic acid cisplatin disulfiram glucose metabolism aldehyde dehydrogenase |
| title | Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells |
| title_full | Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells |
| title_fullStr | Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells |
| title_full_unstemmed | Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells |
| title_short | Valproic acid reprograms the metabolic aberration of cisplatin treatment via ALDH modulation in triple-negative breast cancer cells |
| title_sort | valproic acid reprograms the metabolic aberration of cisplatin treatment via aldh modulation in triple negative breast cancer cells |
| topic | valproic acid cisplatin disulfiram glucose metabolism aldehyde dehydrogenase |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1217149/full |
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