Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors
The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key ro...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-08-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800017 |
| _version_ | 1811299144205074432 |
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| author | Aarif Ahsan Susmita G. Ramanand Christopher Whitehead Susan M. Hiniker Alnawaz Rehemtulla William B. Pratt Shruti Jolly Christopher Gouveia Kristy Truong Carter Van Waes Dipankar Ray Theodore S. Lawrence Mukesh K. Nyati |
| author_facet | Aarif Ahsan Susmita G. Ramanand Christopher Whitehead Susan M. Hiniker Alnawaz Rehemtulla William B. Pratt Shruti Jolly Christopher Gouveia Kristy Truong Carter Van Waes Dipankar Ray Theodore S. Lawrence Mukesh K. Nyati |
| author_sort | Aarif Ahsan |
| collection | DOAJ |
| description | The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone. |
| first_indexed | 2024-04-13T06:30:54Z |
| format | Article |
| id | doaj.art-59e14957f98643cfb68c348498f5b062 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-13T06:30:54Z |
| publishDate | 2012-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-59e14957f98643cfb68c348498f5b0622022-12-22T02:58:08ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-08-0114867067710.1593/neo.12986Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and TumorsAarif Ahsan0Susmita G. Ramanand1Christopher Whitehead2Susan M. Hiniker3Alnawaz Rehemtulla4William B. Pratt5Shruti Jolly6Christopher Gouveia7Kristy Truong8Carter Van Waes9Dipankar Ray10Theodore S. Lawrence11Mukesh K. Nyati12Department of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Radiology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Pharmacology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIHead and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MDHead and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MDHead and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MDDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MIThe epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.http://www.sciencedirect.com/science/article/pii/S1476558612800017 |
| spellingShingle | Aarif Ahsan Susmita G. Ramanand Christopher Whitehead Susan M. Hiniker Alnawaz Rehemtulla William B. Pratt Shruti Jolly Christopher Gouveia Kristy Truong Carter Van Waes Dipankar Ray Theodore S. Lawrence Mukesh K. Nyati Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors Neoplasia: An International Journal for Oncology Research |
| title | Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors |
| title_full | Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors |
| title_fullStr | Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors |
| title_full_unstemmed | Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors |
| title_short | Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors |
| title_sort | wild type egfr is stabilized by direct interaction with hsp90 in cancer cells and tumors |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800017 |
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