Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells
Heat shock protein 90 (Hsp90) is a molecular chaperone important for maintaining protein homeostasis (proteostasis) in the cell. Hsp90 inhibitors are being explored as cancer therapeutics because of their ability to disrupt proteostasis. Inhibiting Hsp90 increases surface density of the immunologica...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1334876/full |
| _version_ | 1827292441081806848 |
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| author | Madison Wickenberg Rebecca Mercier Megan Yap John Walker Kristi Baker Paul LaPointe |
| author_facet | Madison Wickenberg Rebecca Mercier Megan Yap John Walker Kristi Baker Paul LaPointe |
| author_sort | Madison Wickenberg |
| collection | DOAJ |
| description | Heat shock protein 90 (Hsp90) is a molecular chaperone important for maintaining protein homeostasis (proteostasis) in the cell. Hsp90 inhibitors are being explored as cancer therapeutics because of their ability to disrupt proteostasis. Inhibiting Hsp90 increases surface density of the immunological receptor Major Histocompatibility Complex 1 (MHC1). Here we show that this increase occurs across multiple cancer cell lines and with both cytosol-specific and pan-Hsp90 inhibitors. We demonstrate that Hsp90 inhibition also alters surface expression of both IFNGR and PD-L1, two additional immunological receptors that play a significant role in anti-tumour or anti-immune activity in the tumour microenvironment. Hsp90 also negatively regulates IFN-γ activity in cancer cells, suggesting it has a unique role in mediating the immune system’s response to cancer. Our data suggests a strong link between Hsp90 activity and the pathways that govern anti-tumour immunity. This highlights the potential for the use of an Hsp90 inhibitor in combination with another currently available cancer treatment, immune checkpoint blockade therapy, which works to prevent immune evasion of cancer cells. Combination checkpoint inhibitor therapy and the use of an Hsp90 inhibitor may potentiate the therapeutic benefits of both treatments and improve prognosis for cancer patients. |
| first_indexed | 2024-04-24T13:05:52Z |
| format | Article |
| id | doaj.art-0afd9a57c5af4e4e990b6abb435b12a6 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-24T13:05:52Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-0afd9a57c5af4e4e990b6abb435b12a62024-04-05T07:58:08ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2024-04-011110.3389/fmolb.2024.13348761334876Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cellsMadison Wickenberg0Rebecca Mercier1Megan Yap2John Walker3Kristi Baker4Paul LaPointe5Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaDepartment of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaDepartment of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaDepartment of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, CanadaHeat shock protein 90 (Hsp90) is a molecular chaperone important for maintaining protein homeostasis (proteostasis) in the cell. Hsp90 inhibitors are being explored as cancer therapeutics because of their ability to disrupt proteostasis. Inhibiting Hsp90 increases surface density of the immunological receptor Major Histocompatibility Complex 1 (MHC1). Here we show that this increase occurs across multiple cancer cell lines and with both cytosol-specific and pan-Hsp90 inhibitors. We demonstrate that Hsp90 inhibition also alters surface expression of both IFNGR and PD-L1, two additional immunological receptors that play a significant role in anti-tumour or anti-immune activity in the tumour microenvironment. Hsp90 also negatively regulates IFN-γ activity in cancer cells, suggesting it has a unique role in mediating the immune system’s response to cancer. Our data suggests a strong link between Hsp90 activity and the pathways that govern anti-tumour immunity. This highlights the potential for the use of an Hsp90 inhibitor in combination with another currently available cancer treatment, immune checkpoint blockade therapy, which works to prevent immune evasion of cancer cells. Combination checkpoint inhibitor therapy and the use of an Hsp90 inhibitor may potentiate the therapeutic benefits of both treatments and improve prognosis for cancer patients.https://www.frontiersin.org/articles/10.3389/fmolb.2024.1334876/fullcancerchaperonesproteostasisimmunological receptorsHSP90 (heat shock protein 90) |
| spellingShingle | Madison Wickenberg Rebecca Mercier Megan Yap John Walker Kristi Baker Paul LaPointe Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells Frontiers in Molecular Biosciences cancer chaperones proteostasis immunological receptors HSP90 (heat shock protein 90) |
| title | Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| title_full | Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| title_fullStr | Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| title_full_unstemmed | Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| title_short | Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| title_sort | hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells |
| topic | cancer chaperones proteostasis immunological receptors HSP90 (heat shock protein 90) |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1334876/full |
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