Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression
Ovarian cancer is one of the most lethal gynecological malignancies. Recurrence or acquired chemoresistance is the leading cause of ovarian cancer therapy failure. Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1), commonly known as P-glycoprotein, correlates closely with multidrug...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1068443/full |
| _version_ | 1817976005645565952 |
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| author | Wei Huang Wei Huang Shu Yang Yu-Shan Cheng Ni Sima Wei Sun Min Shen John C. Braisted Weiguo Lu Weiguo Lu Wei Zheng |
| author_facet | Wei Huang Wei Huang Shu Yang Yu-Shan Cheng Ni Sima Wei Sun Min Shen John C. Braisted Weiguo Lu Weiguo Lu Wei Zheng |
| author_sort | Wei Huang |
| collection | DOAJ |
| description | Ovarian cancer is one of the most lethal gynecological malignancies. Recurrence or acquired chemoresistance is the leading cause of ovarian cancer therapy failure. Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1), commonly known as P-glycoprotein, correlates closely with multidrug resistance (MDR). However, the mechanism underlying aberrant ABCB1 expression remains unknown. Using a quantitative high-throughput combinational screen, we identified that terfenadine restored doxorubicin sensitivity in an MDR ovarian cancer cell line. In addition, RNA-seq data revealed that the Ca2+-mediated signaling pathway in the MDR cells was abnormally regulated. Moreover, our research demonstrated that terfenadine directly bound to CAMKIID to prevent its autophosphorylation and inhibit the activation of the cAMP-responsive element-binding protein 1 (CREB1)-mediated pathway. Direct inhibition of CAMKII or CREB1 had the same phenotypic effects as terfenadine in the combined treatment, including lower expression of ABCB1 and baculoviral IAP repeat-containing 5 (BIRC5, also known as survivin) and increased doxorubicin-induced apoptosis. In this study, we demonstrate that aberrant regulation of the Ca2+-mediated CAMKIID/CREB1 pathway contributes to ABCB1 over-expression and MDR creation and that CAMKIID and CREB1 are attractive targets for restoring doxorubicin efficacy in ABCB1-mediated MDR ovarian cancer. |
| first_indexed | 2024-04-13T21:56:51Z |
| format | Article |
| id | doaj.art-de4f31316fb743f480290694cb75b5e8 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T21:56:51Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-de4f31316fb743f480290694cb75b5e82022-12-22T02:28:13ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.10684431068443Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expressionWei Huang0Wei Huang1Shu Yang2Yu-Shan Cheng3Ni Sima4Wei Sun5Min Shen6John C. Braisted7Weiguo Lu8Weiguo Lu9Wei Zheng10Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesWomen’s Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesWomen’s Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaWomen’s Reproductive Health Research Laboratory of Zhejiang Province, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United StatesOvarian cancer is one of the most lethal gynecological malignancies. Recurrence or acquired chemoresistance is the leading cause of ovarian cancer therapy failure. Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1), commonly known as P-glycoprotein, correlates closely with multidrug resistance (MDR). However, the mechanism underlying aberrant ABCB1 expression remains unknown. Using a quantitative high-throughput combinational screen, we identified that terfenadine restored doxorubicin sensitivity in an MDR ovarian cancer cell line. In addition, RNA-seq data revealed that the Ca2+-mediated signaling pathway in the MDR cells was abnormally regulated. Moreover, our research demonstrated that terfenadine directly bound to CAMKIID to prevent its autophosphorylation and inhibit the activation of the cAMP-responsive element-binding protein 1 (CREB1)-mediated pathway. Direct inhibition of CAMKII or CREB1 had the same phenotypic effects as terfenadine in the combined treatment, including lower expression of ABCB1 and baculoviral IAP repeat-containing 5 (BIRC5, also known as survivin) and increased doxorubicin-induced apoptosis. In this study, we demonstrate that aberrant regulation of the Ca2+-mediated CAMKIID/CREB1 pathway contributes to ABCB1 over-expression and MDR creation and that CAMKIID and CREB1 are attractive targets for restoring doxorubicin efficacy in ABCB1-mediated MDR ovarian cancer.https://www.frontiersin.org/articles/10.3389/fonc.2022.1068443/fulldrug-resistantovarian cancerterfenadineCaMKIIdoxorubicin |
| spellingShingle | Wei Huang Wei Huang Shu Yang Yu-Shan Cheng Ni Sima Wei Sun Min Shen John C. Braisted Weiguo Lu Weiguo Lu Wei Zheng Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression Frontiers in Oncology drug-resistant ovarian cancer terfenadine CaMKII doxorubicin |
| title | Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression |
| title_full | Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression |
| title_fullStr | Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression |
| title_full_unstemmed | Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression |
| title_short | Terfenadine resensitizes doxorubicin activity in drug-resistant ovarian cancer cells via an inhibition of CaMKII/CREB1 mediated ABCB1 expression |
| title_sort | terfenadine resensitizes doxorubicin activity in drug resistant ovarian cancer cells via an inhibition of camkii creb1 mediated abcb1 expression |
| topic | drug-resistant ovarian cancer terfenadine CaMKII doxorubicin |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1068443/full |
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