Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration
Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using different...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/2/212 |
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| author | Attila Varga Minh Tu Nguyen Kinga Pénzes Bence Bátai Pál Gyulavári Bianka Gurbi József Murányi Péter Csermely Miklós Csala Tibor Vántus Csaba Sőti |
| author_facet | Attila Varga Minh Tu Nguyen Kinga Pénzes Bence Bátai Pál Gyulavári Bianka Gurbi József Murányi Péter Csermely Miklós Csala Tibor Vántus Csaba Sőti |
| author_sort | Attila Varga |
| collection | DOAJ |
| description | Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using different prostate cancer cell lines, we report that Hsp90 ensures PKD3 conformational stability and function to promote cancer cell migration. We found that pharmacological inhibition of either PKDs or Hsp90 dose-dependently abrogated the migration of DU145 and PC3 metastatic prostate cancer cells. Hsp90 inhibition by ganetespib caused a dose-dependent depletion of PKD2, PKD3, and Akt, which are all involved in metastasis formation. Proximity ligation assay and immunoprecipitation experiments demonstrated a physical interaction between Hsp90 and PKD3. Inhibition of the chaperone–client interaction induced misfolding and proteasomal degradation of PKD3. PKD3 siRNA combined with ganetespib treatment demonstrated a specific involvement of PKD3 in DU145 and PC3 cell migration, which was entirely dependent on Hsp90. Finally, ectopic expression of PKD3 enhanced migration of non-metastatic LNCaP cells in an Hsp90-dependent manner. Altogether, our findings identify PKD3 as an Hsp90 client and uncover a potential mechanism of Hsp90 in prostate cancer metastasis. The molecular interaction revealed here may regulate other biological and pathological functions. |
| first_indexed | 2024-03-09T13:13:29Z |
| format | Article |
| id | doaj.art-a25c4d7aca6d4c5f82f3e3ec898a3af3 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T13:13:29Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a25c4d7aca6d4c5f82f3e3ec898a3af32023-11-30T21:39:05ZengMDPI AGCells2073-44092023-01-0112221210.3390/cells12020212Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell MigrationAttila Varga0Minh Tu Nguyen1Kinga Pénzes2Bence Bátai3Pál Gyulavári4Bianka Gurbi5József Murányi6Péter Csermely7Miklós Csala8Tibor Vántus9Csaba Sőti10Department of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryDepartment of Molecular Biology, Semmelweis University, 1094 Budapest, HungaryProstate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using different prostate cancer cell lines, we report that Hsp90 ensures PKD3 conformational stability and function to promote cancer cell migration. We found that pharmacological inhibition of either PKDs or Hsp90 dose-dependently abrogated the migration of DU145 and PC3 metastatic prostate cancer cells. Hsp90 inhibition by ganetespib caused a dose-dependent depletion of PKD2, PKD3, and Akt, which are all involved in metastasis formation. Proximity ligation assay and immunoprecipitation experiments demonstrated a physical interaction between Hsp90 and PKD3. Inhibition of the chaperone–client interaction induced misfolding and proteasomal degradation of PKD3. PKD3 siRNA combined with ganetespib treatment demonstrated a specific involvement of PKD3 in DU145 and PC3 cell migration, which was entirely dependent on Hsp90. Finally, ectopic expression of PKD3 enhanced migration of non-metastatic LNCaP cells in an Hsp90-dependent manner. Altogether, our findings identify PKD3 as an Hsp90 client and uncover a potential mechanism of Hsp90 in prostate cancer metastasis. The molecular interaction revealed here may regulate other biological and pathological functions.https://www.mdpi.com/2073-4409/12/2/212protein kinase Dheat shock protein 90prostate cancermigrationmetastasis |
| spellingShingle | Attila Varga Minh Tu Nguyen Kinga Pénzes Bence Bátai Pál Gyulavári Bianka Gurbi József Murányi Péter Csermely Miklós Csala Tibor Vántus Csaba Sőti Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration Cells protein kinase D heat shock protein 90 prostate cancer migration metastasis |
| title | Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration |
| title_full | Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration |
| title_fullStr | Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration |
| title_full_unstemmed | Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration |
| title_short | Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration |
| title_sort | protein kinase d3 pkd3 requires hsp90 for stability and promotion of prostate cancer cell migration |
| topic | protein kinase D heat shock protein 90 prostate cancer migration metastasis |
| url | https://www.mdpi.com/2073-4409/12/2/212 |
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