PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro
Metastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In...
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MDPI AG
2021-02-01
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| Series: | Marine Drugs |
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| Online Access: | https://www.mdpi.com/1660-3397/19/2/117 |
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| author | Aotong Zhang Xin Qi Fu Du Guojian Zhang Dehai Li Jing Li |
| author_facet | Aotong Zhang Xin Qi Fu Du Guojian Zhang Dehai Li Jing Li |
| author_sort | Aotong Zhang |
| collection | DOAJ |
| description | Metastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In the present study, we investigated the inhibitory effect of penisuloxazin A (PNSA), a novel C- terminal inhibitor of HSP90, on metastasis of breast cancer cells and related mechanism in vitro. We found that PNSA obviously affected adhesion, migration, and invasion of triple-negative breast cancer (TNBC) MDA-MB-231 cells and Trastuzumab-resistant JIMT-1 cells. Furthermore, PNSA was capable of reversing epithelial–mesenchymal transformation (EMT) of MDA-MB-231 cells with change of cell morphology. PNSA increases E-cadherin expression followed by decreasing amounts of N-cadherin, vimentin, and matrix metalloproteinases9 (MMP9) and proteolytic activity of matrix metalloproteinases2 (MMP2) and MMP9. Comparatively, the N-terminal inhibitor of HSP90 17-allyl-17-demethoxygeldanamycin (17-AAG) had no effect on EMT of MDA-MB-231 cells. PNSA was uncovered to reduce the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) proteins and thereby inhibiting their downstream signaling transductions by inhibition of HSP90. In addition, PNSA reduced the expression of programmed cell death-ligand 1 (PD-L1) to promote natural killer (NK) cells to kill breast cancer cells with a dose far less than that of cytotoxicity to NK cell itself, implying the potential of PNSA to enhance immune surveillance against metastasis in vivo. All these results indicate that PNSA is a promising anti-metastasis agent worthy of being studied in the future. |
| first_indexed | 2024-03-09T00:41:17Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-09T00:41:17Z |
| publishDate | 2021-02-01 |
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| series | Marine Drugs |
| spelling | doaj.art-14a5aa4fd08546269cbc9456cdca16812023-12-11T17:46:16ZengMDPI AGMarine Drugs1660-33972021-02-0119211710.3390/md19020117PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In VitroAotong Zhang0Xin Qi1Fu Du2Guojian Zhang3Dehai Li4Jing Li5Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaMetastasis accounts for the vast majority of deaths in breast cancer, and novel and effective treatments to inhibit cancer metastasis remain urgently developed. The expression level of heat shock protein 90 (HSP90) in invasive breast cancer tissue is higher than in adjacent non-cancerous tissue. In the present study, we investigated the inhibitory effect of penisuloxazin A (PNSA), a novel C- terminal inhibitor of HSP90, on metastasis of breast cancer cells and related mechanism in vitro. We found that PNSA obviously affected adhesion, migration, and invasion of triple-negative breast cancer (TNBC) MDA-MB-231 cells and Trastuzumab-resistant JIMT-1 cells. Furthermore, PNSA was capable of reversing epithelial–mesenchymal transformation (EMT) of MDA-MB-231 cells with change of cell morphology. PNSA increases E-cadherin expression followed by decreasing amounts of N-cadherin, vimentin, and matrix metalloproteinases9 (MMP9) and proteolytic activity of matrix metalloproteinases2 (MMP2) and MMP9. Comparatively, the N-terminal inhibitor of HSP90 17-allyl-17-demethoxygeldanamycin (17-AAG) had no effect on EMT of MDA-MB-231 cells. PNSA was uncovered to reduce the stability of epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) proteins and thereby inhibiting their downstream signaling transductions by inhibition of HSP90. In addition, PNSA reduced the expression of programmed cell death-ligand 1 (PD-L1) to promote natural killer (NK) cells to kill breast cancer cells with a dose far less than that of cytotoxicity to NK cell itself, implying the potential of PNSA to enhance immune surveillance against metastasis in vivo. All these results indicate that PNSA is a promising anti-metastasis agent worthy of being studied in the future.https://www.mdpi.com/1660-3397/19/2/117HSP90inhibitorEMTmetastasisbreast cancer |
| spellingShingle | Aotong Zhang Xin Qi Fu Du Guojian Zhang Dehai Li Jing Li PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro Marine Drugs HSP90 inhibitor EMT metastasis breast cancer |
| title | PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro |
| title_full | PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro |
| title_fullStr | PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro |
| title_full_unstemmed | PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro |
| title_short | PNSA, a Novel C-Terminal Inhibitor of HSP90, Reverses Epithelial–Mesenchymal Transition and Suppresses Metastasis of Breast Cancer Cells In Vitro |
| title_sort | pnsa a novel c terminal inhibitor of hsp90 reverses epithelial mesenchymal transition and suppresses metastasis of breast cancer cells in vitro |
| topic | HSP90 inhibitor EMT metastasis breast cancer |
| url | https://www.mdpi.com/1660-3397/19/2/117 |
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