PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma
Abstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant chall...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-85289-0 |
| _version_ | 1818430796942278656 |
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| author | Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle |
| author_facet | Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle |
| author_sort | Raoud Marayati |
| collection | DOAJ |
| description | Abstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54–80% of patients developing resistance to chemotherapy after 4–5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse. |
| first_indexed | 2024-12-14T15:39:07Z |
| format | Article |
| id | doaj.art-651d99d3286c48f987b6b07498bbc8c8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:39:07Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-651d99d3286c48f987b6b07498bbc8c82022-12-21T22:55:40ZengNature PortfolioScientific Reports2045-23222021-03-0111111410.1038/s41598-021-85289-0PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastomaRaoud Marayati0Laura L. Stafman1Adele P. Williams2Laura V. Bownes3Colin H. Quinn4Jamie M. Aye5Jerry E. Stewart6Karina J. Yoon7Joshua C. Anderson8Christopher D. Willey9Elizabeth A. Beierle10Department of Surgery, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamDepartment of Pediatric Hematology Oncology, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamDepartment of Pharmacology and Toxicology, University of Alabama at BirminghamDepartment of Radiation Oncology, University of Alabama at BirminghamDepartment of Radiation Oncology, University of Alabama at BirminghamDepartment of Surgery, University of Alabama at BirminghamAbstract Despite increasing incidence, treatment for hepatoblastoma has not changed significantly over the past 20 years. Chemotherapeutic strategies continue to rely on cisplatin, as it remains the most active single agent against hepatoblastoma. However, chemoresistance remains a significant challenge with 54–80% of patients developing resistance to chemotherapy after 4–5 cycles of treatment. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to play a role in chemoresistance and disease recurrence. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM) kinases, specifically PIM3, play a role in hepatoblastoma cell proliferation and tumor growth and maintain the SCLCC phenotype. Here, we describe the development of a cisplatin-resistant hepatoblastoma xenograft model of the human HuH6 cell line and a patient-derived xenograft, COA67. We provide evidence that these cisplatin-resistant cells are enriched for SCLCCs and express PIM3 at higher levels than cisplatin-naïve cells. We demonstrate that PIM inhibition with AZD1208 sensitizes cisplatin-resistant hepatoblastoma cells to cisplatin, enhances cisplatin-mediated apoptosis, and decreases the SCLCC phenotype seen with cisplatin resistance. Together, these findings indicate that PIM inhibition may be a promising adjunct in the treatment of hepatoblastoma to effectively target SCLCCs and potentially decrease chemoresistance and subsequent disease relapse.https://doi.org/10.1038/s41598-021-85289-0 |
| spellingShingle | Raoud Marayati Laura L. Stafman Adele P. Williams Laura V. Bownes Colin H. Quinn Jamie M. Aye Jerry E. Stewart Karina J. Yoon Joshua C. Anderson Christopher D. Willey Elizabeth A. Beierle PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma Scientific Reports |
| title | PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| title_full | PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| title_fullStr | PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| title_full_unstemmed | PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| title_short | PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| title_sort | pim kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma |
| url | https://doi.org/10.1038/s41598-021-85289-0 |
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