Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers
The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hypera...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/10/2795 |
| _version_ | 1797552263532642304 |
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| author | Aadhya Tiwari Mari Iida Corinna Kosnopfel Mahyar Abbariki Apostolos Menegakis Birgit Fehrenbacher Julia Maier Martin Schaller Sara Y. Brucker Deric L. Wheeler Paul M. Harari Ulrich Rothbauer Birgit Schittek Daniel Zips Mahmoud Toulany |
| author_facet | Aadhya Tiwari Mari Iida Corinna Kosnopfel Mahyar Abbariki Apostolos Menegakis Birgit Fehrenbacher Julia Maier Martin Schaller Sara Y. Brucker Deric L. Wheeler Paul M. Harari Ulrich Rothbauer Birgit Schittek Daniel Zips Mahmoud Toulany |
| author_sort | Aadhya Tiwari |
| collection | DOAJ |
| description | The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in <i>KRAS</i> mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (<i>PIK3CA</i>). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in <i>KRAS(G13D)</i>-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus <i>PIK3CA(H1047R)</i>/<i>PTEN(E307K)</i> mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in <i>KRAS</i>-mutated cells is mainly dependent on the MAPK/ERK pathway, while in <i>PIK3CA</i>/<i>PTEN</i>-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC. |
| first_indexed | 2024-03-10T15:57:32Z |
| format | Article |
| id | doaj.art-145fc2c3ce1d4a3a9bf0b533a10575f9 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:57:32Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-145fc2c3ce1d4a3a9bf0b533a10575f92023-11-20T15:29:21ZengMDPI AGCancers2072-66942020-09-011210279510.3390/cancers12102795Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast CancersAadhya Tiwari0Mari Iida1Corinna Kosnopfel2Mahyar Abbariki3Apostolos Menegakis4Birgit Fehrenbacher5Julia Maier6Martin Schaller7Sara Y. Brucker8Deric L. Wheeler9Paul M. Harari10Ulrich Rothbauer11Birgit Schittek12Daniel Zips13Mahmoud Toulany14Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Human Oncology, University of Wisconsin, Madison, WI 53705, USADepartment of Dermatology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Human Oncology, University of Wisconsin, Madison, WI 53705, USADepartment of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Dermatology, University of Tuebingen, 72076 Tuebingen, GermanyNatural and Medical Sciences Institute, University of Tuebingen, 72770 Reutlingen, GermanyDepartment of Dermatology, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Women’s Health, University of Tuebingen, 72076 Tuebingen, GermanyDepartment of Human Oncology, University of Wisconsin, Madison, WI 53705, USADepartment of Human Oncology, University of Wisconsin, Madison, WI 53705, USANatural and Medical Sciences Institute, University of Tuebingen, 72770 Reutlingen, GermanyDepartment of Dermatology, University of Tuebingen, 72076 Tuebingen, GermanyDivision of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyDivision of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, 72076 Tuebingen, GermanyThe multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in <i>KRAS</i> mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (<i>PIK3CA</i>). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in <i>KRAS(G13D)</i>-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus <i>PIK3CA(H1047R)</i>/<i>PTEN(E307K)</i> mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in <i>KRAS</i>-mutated cells is mainly dependent on the MAPK/ERK pathway, while in <i>PIK3CA</i>/<i>PTEN</i>-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.https://www.mdpi.com/2072-6694/12/10/2795triple negative breast cancer cellsKRASPTENPIK3CAYB-1MAPK/ERK |
| spellingShingle | Aadhya Tiwari Mari Iida Corinna Kosnopfel Mahyar Abbariki Apostolos Menegakis Birgit Fehrenbacher Julia Maier Martin Schaller Sara Y. Brucker Deric L. Wheeler Paul M. Harari Ulrich Rothbauer Birgit Schittek Daniel Zips Mahmoud Toulany Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers Cancers triple negative breast cancer cells KRAS PTEN PIK3CA YB-1 MAPK/ERK |
| title | Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers |
| title_full | Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers |
| title_fullStr | Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers |
| title_full_unstemmed | Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers |
| title_short | Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers |
| title_sort | blocking y box binding protein 1 through simultaneous targeting of pi3k and mapk in triple negative breast cancers |
| topic | triple negative breast cancer cells KRAS PTEN PIK3CA YB-1 MAPK/ERK |
| url | https://www.mdpi.com/2072-6694/12/10/2795 |
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