Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway
| Autor: | Gary K. Koski, Amrita Basu, Payal Grover, Qianxing Mo, Hatem Soliman, Brian J. Czerniecki, Hyo S. Han, Mark I. Greene, Doris Wiener, Colin Snyder, Hongtao Zhang, Yong-Zi Chen, Jose R. Conejo-Garcia, Ricardo Costa, Ganesan Ramamoorthi, Zhongsheng Tong, Krithika Kodumudi, Catherine A. Lee, Shari Pilon-Thomas, Yongsheng Jia |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Senescence
Chaperonins Receptor ErbB-2 Breast Neoplasms Cell Cycle Proteins Interferon-gamma 03 medical and health sciences 0302 clinical medicine Immune system Interferon Cell Line Tumor Heat shock protein Drug Discovery Genetics medicine Humans Interferon gamma skin and connective tissue diseases neoplasms Molecular Biology Cellular Senescence 030304 developmental biology Pharmacology 0303 health sciences biology Chemistry Vaccination Th1 Cells Cullin Proteins Ubiquitin ligase Gene Expression Regulation Neoplastic Ubiquitin-Proteasomal Pathway 030220 oncology & carcinogenesis Proteolysis biology.protein Cancer research Cytokines Molecular Medicine Female CUL5 medicine.drug |
| Zdroj: | Molecular Therapy. 29:1541-1556 |
| ISSN: | 1525-0016 |
| Popis: | HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|