Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib
Xiaowen Chen, Zhenqi Huang, Wei Wu, Ruixiang Xia Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of ChinaCorrespondence: Ruixiang Xia Email xiaruixiang@ahmu.edu.cnIntroduction: Skp2 is an E3 ubiquitin ligase that p...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2020-06-01
|
| Series: | Cancer Management and Research |
| Subjects: | |
| Online Access: | https://www.dovepress.com/inhibition-of-skp2-sensitizes-chronic-myeloid-leukemia-cells-to-imatin-peer-reviewed-article-CMAR |
| _version_ | 1828861892319248384 |
|---|---|
| author | Chen X Huang Z Wu W Xia R |
| author_facet | Chen X Huang Z Wu W Xia R |
| author_sort | Chen X |
| collection | DOAJ |
| description | Xiaowen Chen, Zhenqi Huang, Wei Wu, Ruixiang Xia Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of ChinaCorrespondence: Ruixiang Xia Email xiaruixiang@ahmu.edu.cnIntroduction: Skp2 is an E3 ubiquitin ligase that plays an important role in modulating tumor progression. The mechanisms underlying Skp2 in the promotion of proliferation and its function in the primary resistance to tyrosine kinase inhibitors (TKIs) in human CML remain to be determined. This study aimed to investigate the function of Skp2 in CML progression as well as its effects on TKI sensitivity.Methods: Expression of Skp2 in leukocytes from patients with CML and normal blood samples was analyzed by qRT-PCR. Cell proliferation was analyzed by EdU incorporation and cell counting assays. Luciferase reporter and chromatin immunoprecipitation assays were used for examination of the effects of CREB on Skp2 expression. The apoptosis in vitro of K562 cells was analyzed by MTT and caspase 3/7 activity assays.Results: The present study demonstrates that Skp2 was expressed at a higher level in patients with CML compared with healthy donors, and the elevated expression of Skp2 is critical for CML cell proliferation. Mechanistically, Skp2 was transcriptionally upregulated by CREB responsive to the PI3K/Akt signaling pathway. Furthermore, inhibition of Skp2 expression by shRNAs or blocking the PI3K/Akt/CREB pathway greatly enhances the sensitivity of CML cells to Imatinib treatment.Conclusion: We conclude that the PI3K/Akt/CREB axis regulates the sensitivity of K562 cells to Imatinib via mediating Skp2 expression. The present study revealed an unknown role of Skp2 in CML progression and provided new aspects on the Skp2-modulated TKI sensitivity in CML, contributing to the development of potential therapeutic anticancer drugs.Keywords: Skp2, PI3K/Akt, CREB, Imatinib |
| first_indexed | 2024-12-13T03:12:47Z |
| format | Article |
| id | doaj.art-44384072af8c43b5924dfdbf955dab3b |
| institution | Directory Open Access Journal |
| issn | 1179-1322 |
| language | English |
| last_indexed | 2024-12-13T03:12:47Z |
| publishDate | 2020-06-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Cancer Management and Research |
| spelling | doaj.art-44384072af8c43b5924dfdbf955dab3b2022-12-22T00:01:34ZengDove Medical PressCancer Management and Research1179-13222020-06-01Volume 124777478754709Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to ImatinibChen XHuang ZWu WXia RXiaowen Chen, Zhenqi Huang, Wei Wu, Ruixiang Xia Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, People’s Republic of ChinaCorrespondence: Ruixiang Xia Email xiaruixiang@ahmu.edu.cnIntroduction: Skp2 is an E3 ubiquitin ligase that plays an important role in modulating tumor progression. The mechanisms underlying Skp2 in the promotion of proliferation and its function in the primary resistance to tyrosine kinase inhibitors (TKIs) in human CML remain to be determined. This study aimed to investigate the function of Skp2 in CML progression as well as its effects on TKI sensitivity.Methods: Expression of Skp2 in leukocytes from patients with CML and normal blood samples was analyzed by qRT-PCR. Cell proliferation was analyzed by EdU incorporation and cell counting assays. Luciferase reporter and chromatin immunoprecipitation assays were used for examination of the effects of CREB on Skp2 expression. The apoptosis in vitro of K562 cells was analyzed by MTT and caspase 3/7 activity assays.Results: The present study demonstrates that Skp2 was expressed at a higher level in patients with CML compared with healthy donors, and the elevated expression of Skp2 is critical for CML cell proliferation. Mechanistically, Skp2 was transcriptionally upregulated by CREB responsive to the PI3K/Akt signaling pathway. Furthermore, inhibition of Skp2 expression by shRNAs or blocking the PI3K/Akt/CREB pathway greatly enhances the sensitivity of CML cells to Imatinib treatment.Conclusion: We conclude that the PI3K/Akt/CREB axis regulates the sensitivity of K562 cells to Imatinib via mediating Skp2 expression. The present study revealed an unknown role of Skp2 in CML progression and provided new aspects on the Skp2-modulated TKI sensitivity in CML, contributing to the development of potential therapeutic anticancer drugs.Keywords: Skp2, PI3K/Akt, CREB, Imatinibhttps://www.dovepress.com/inhibition-of-skp2-sensitizes-chronic-myeloid-leukemia-cells-to-imatin-peer-reviewed-article-CMARskp2pi3k/aktcrebimatinib |
| spellingShingle | Chen X Huang Z Wu W Xia R Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib Cancer Management and Research skp2 pi3k/akt creb imatinib |
| title | Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib |
| title_full | Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib |
| title_fullStr | Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib |
| title_full_unstemmed | Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib |
| title_short | Inhibition of Skp2 Sensitizes Chronic Myeloid Leukemia Cells to Imatinib |
| title_sort | inhibition of skp2 sensitizes chronic myeloid leukemia cells to imatinib |
| topic | skp2 pi3k/akt creb imatinib |
| url | https://www.dovepress.com/inhibition-of-skp2-sensitizes-chronic-myeloid-leukemia-cells-to-imatin-peer-reviewed-article-CMAR |
| work_keys_str_mv | AT chenx inhibitionofskp2sensitizeschronicmyeloidleukemiacellstoimatinib AT huangz inhibitionofskp2sensitizeschronicmyeloidleukemiacellstoimatinib AT wuw inhibitionofskp2sensitizeschronicmyeloidleukemiacellstoimatinib AT xiar inhibitionofskp2sensitizeschronicmyeloidleukemiacellstoimatinib |