Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
Abstract Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment‐dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non‐genetic resistance mechanisms was long neglecte...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911177 |
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| author | Lidia Moyano‐Galceran Elina A Pietilä S Pauliina Turunen Sara Corvigno Elisabet Hjerpe Daria Bulanova Ulrika Joneborg Twana Alkasalias Yuichiro Miki Masakazu Yashiro Anastasiya Chernenko Joonas Jukonen Madhurendra Singh Hanna Dahlstrand Joseph W Carlson Kaisa Lehti |
| author_facet | Lidia Moyano‐Galceran Elina A Pietilä S Pauliina Turunen Sara Corvigno Elisabet Hjerpe Daria Bulanova Ulrika Joneborg Twana Alkasalias Yuichiro Miki Masakazu Yashiro Anastasiya Chernenko Joonas Jukonen Madhurendra Singh Hanna Dahlstrand Joseph W Carlson Kaisa Lehti |
| author_sort | Lidia Moyano‐Galceran |
| collection | DOAJ |
| description | Abstract Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment‐dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non‐genetic resistance mechanisms was long neglected. Using high‐grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy‐induced ERK1/2‐RSK1/2‐EphA2‐GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2‐S897 phosphorylation and EphA2‐GPRC5A co‐regulation, thereby facilitating a signaling shift to the canonical tumor‐suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum‐resistant EphA2high, GPRC5Ahigh cells to the therapy‐induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo‐resistant cells to RSK1/2‐EphA2‐pS897 pathway inhibition. |
| format | Article |
| id | doaj-art-53a1f3dd95a442a0b1b984d8469f054e |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-53a1f3dd95a442a0b1b984d8469f054e2025-08-24T11:44:11ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-03-0112412210.15252/emmm.201911177Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancerLidia Moyano‐Galceran0Elina A Pietilä1S Pauliina Turunen2Sara Corvigno3Elisabet Hjerpe4Daria Bulanova5Ulrika Joneborg6Twana Alkasalias7Yuichiro Miki8Masakazu Yashiro9Anastasiya Chernenko10Joonas Jukonen11Madhurendra Singh12Hanna Dahlstrand13Joseph W Carlson14Kaisa Lehti15Department of Microbiology, Tumor and Cell Biology, Karolinska InstitutetResearch Programs Unit, Individualized Drug Therapy, University of Helsinki and Helsinki University HospitalDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Oncology and Pathology, Karolinska InstitutetDepartment of Obstetrics and Gynecology, Visby HospitalInstitute for Molecular Medicine Finland, FIMM, University of HelsinkiDivision of Pelvic Cancer, Department of Women's and Children's Health, Karolinska Institutet and University HospitalDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Gastroenterological Surgery, Osaka City University Graduate School of MedicineResearch Programs Unit, Individualized Drug Therapy, University of Helsinki and Helsinki University HospitalResearch Programs Unit, Individualized Drug Therapy, University of Helsinki and Helsinki University HospitalDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetDepartment of Oncology and Pathology, Karolinska InstitutetDepartment of Oncology and Pathology, Karolinska InstitutetDepartment of Microbiology, Tumor and Cell Biology, Karolinska InstitutetAbstract Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment‐dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non‐genetic resistance mechanisms was long neglected. Using high‐grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy‐induced ERK1/2‐RSK1/2‐EphA2‐GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2‐S897 phosphorylation and EphA2‐GPRC5A co‐regulation, thereby facilitating a signaling shift to the canonical tumor‐suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum‐resistant EphA2high, GPRC5Ahigh cells to the therapy‐induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo‐resistant cells to RSK1/2‐EphA2‐pS897 pathway inhibition.https://doi.org/10.15252/emmm.201911177chemotherapyEphA2GPRC5AHGSCresistance |
| spellingShingle | Lidia Moyano‐Galceran Elina A Pietilä S Pauliina Turunen Sara Corvigno Elisabet Hjerpe Daria Bulanova Ulrika Joneborg Twana Alkasalias Yuichiro Miki Masakazu Yashiro Anastasiya Chernenko Joonas Jukonen Madhurendra Singh Hanna Dahlstrand Joseph W Carlson Kaisa Lehti Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer EMBO Molecular Medicine chemotherapy EphA2 GPRC5A HGSC resistance |
| title | Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer |
| title_full | Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer |
| title_fullStr | Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer |
| title_full_unstemmed | Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer |
| title_short | Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer |
| title_sort | adaptive rsk epha2 gprc5a signaling switch triggers chemotherapy resistance in ovarian cancer |
| topic | chemotherapy EphA2 GPRC5A HGSC resistance |
| url | https://doi.org/10.15252/emmm.201911177 |
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