Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance
USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/22/8629 |
| _version_ | 1797547784126070784 |
|---|---|
| author | Sol-Bi Shin Chang-Hyeon Kim Hay-Ran Jang Hyungshin Yim |
| author_facet | Sol-Bi Shin Chang-Hyeon Kim Hay-Ran Jang Hyungshin Yim |
| author_sort | Sol-Bi Shin |
| collection | DOAJ |
| description | USP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460<sup>TXR</sup> cells, which has resistance to mitotic catastrophe, NCI-H460<sup>TXR</sup> cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of <i>MDR1/ABCB1</i> in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism. |
| first_indexed | 2024-03-10T14:49:07Z |
| format | Article |
| id | doaj.art-b7b2b673fe32479baa6f8264e11c6398 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:49:07Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b7b2b673fe32479baa6f8264e11c63982023-11-20T21:08:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122862910.3390/ijms21228629Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel ResistanceSol-Bi Shin0Chang-Hyeon Kim1Hay-Ran Jang2Hyungshin Yim3Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaDepartment of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, KoreaUSP7 is a promising target for the development of cancer treatments because of its high expression and the critical functions of its substrates in carcinogenesis of several different carcinomas. Here, we demonstrated the effectiveness of targeting USP7 in advanced malignant cells showing high levels of USP7, especially in taxane-resistant cancer. USP7 knockdown effectively induced cell death in several cancer cells of lung, prostate, and cervix. Depletion of USP7 induced multiple spindle pole formation in mitosis, and, consequently, resulted in mitotic catastrophe. When USP7 was blocked in the paclitaxel-resistant lung cancer NCI-H460<sup>TXR</sup> cells, which has resistance to mitotic catastrophe, NCI-H460<sup>TXR</sup> cells underwent apoptosis effectively. Furthermore, combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the USP7 inhibitor P22077 showed a strong synergism through down-regulation of <i>MDR1/ABCB1</i> in paclitaxel-resistant lung cancer. Therefore, we suggest USP7 is a promising target for cancer therapy, and combination therapy with inhibitors of PLK1 and USP7 may be valuable for treating paclitaxel-resistant cancers, because of their strong synergism.https://www.mdpi.com/1422-0067/21/22/8629USP7PLK1taxanechemoresistancecombination |
| spellingShingle | Sol-Bi Shin Chang-Hyeon Kim Hay-Ran Jang Hyungshin Yim Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance International Journal of Molecular Sciences USP7 PLK1 taxane chemoresistance combination |
| title | Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance |
| title_full | Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance |
| title_fullStr | Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance |
| title_full_unstemmed | Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance |
| title_short | Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance |
| title_sort | combination of inhibitors of usp7 and plk1 has a strong synergism against paclitaxel resistance |
| topic | USP7 PLK1 taxane chemoresistance combination |
| url | https://www.mdpi.com/1422-0067/21/22/8629 |
| work_keys_str_mv | AT solbishin combinationofinhibitorsofusp7andplk1hasastrongsynergismagainstpaclitaxelresistance AT changhyeonkim combinationofinhibitorsofusp7andplk1hasastrongsynergismagainstpaclitaxelresistance AT hayranjang combinationofinhibitorsofusp7andplk1hasastrongsynergismagainstpaclitaxelresistance AT hyungshinyim combinationofinhibitorsofusp7andplk1hasastrongsynergismagainstpaclitaxelresistance |