Journal of cellular physiology, 2021-09, Vol.236 (9), p.6481-6495
2021
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- Autor(en) / Beteiligte
- Titel
- ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer
- Ist Teil von
- Journal of cellular physiology, 2021-09, Vol.236 (9), p.6481-6495
- Ort / Verlag
- United States: Wiley Subscription Services, Inc
- Erscheinungsjahr
- 2021
- Quelle
- Wiley Online Library Journals Frontfile Complete
- Beschreibungen/Notizen
- AAA domain containing 3A (ATAD3A) is a nucleus‐encoded mitochondrial protein with vital function in communication between endoplasmic reticulum (ER) and mitochondria which is participated in cancer metastasis. Here we show that elevated ATAD3A expression is clinically associated with poor 5‐year disease‐free survival in patients with colorectal cancer (CRC), especially high‐risk CRC patients who received adjuvant chemotherapy. Our results indicated ATAD3A is significantly upregulated to reduce chemotherapy‐induced cancer cell death. We found that knockdown of ATAD3A leads to dysregulation in protein processing for inducing ER stress by RNA sequencing (RNA‐seq). In response to chemotherapy‐induced ER stress, ATAD3A interacts with elevated GRP78 protein to assist protein folding and alleviate ER stress for cancer cell survival. This reduction of ER stress leads to reduce the surface exposure of calreticulin, which is the initiator of immunogenic cell death and antitumor immunity. However, silencing of ATAD3A enhances cell death, triggers the feasibility of chemotherapy‐induced ER stress for antitumor immunity, increases infiltration of T lymphocytes and delays tumor regrowth in vitro and in vivo. Clinically, CRC patients with less ATAD3A have high density of CD45+ intratumoral infiltrating lymphocytes (TILs) and memory CD45RO+ TILs. Taken together, our results suggest that pharmacologic targeting to ATAD3A might be a potential therapeutic strategy to enhance antitumor immunity for CRC patients who received adjuvant chemotherapy. 1. ATAD3A directly interactes with GRP78 to reduce chemotherapy‐induced ER stress response. 2. High ATAD3A may alleviate chemotherapy‐induced immunogenic cell death and reduce the recruitment of T cells for anticancer immune response. 3. Patient with high ATAD3A expression was conversely associated with the density of CD45+ and CD45RO T cell infiltration, and associated with poor survival outcome.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9541eISSN: 1097-4652DOI: 10.1002/jcp.30323Titel-ID: cdi_proquest_miscellaneous_2489253036
- Format
- –
- Schlagworte
- Aged, Animals, Apoptosis, ATPase family AAA domain containing 3A (ATAD3A), ATPases Associated with Diverse Cellular Activities - metabolism, Calreticulin, Cancer, CD45 antigen, Cell death, Cell Line, Tumor, Cell survival, Chemoresistance, Chemotherapy, colon carcinoma, Colorectal cancer, Colorectal carcinoma, Colorectal Neoplasms - drug therapy, Colorectal Neoplasms - immunology, Colorectal Neoplasms - metabolism, Colorectal Neoplasms - pathology, Disease-Free Survival, Drug Resistance, Neoplasm - drug effects, Endoplasmic reticulum, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress - drug effects, ER stress, Female, Gene sequencing, glucose‐regulated protein 78 kDa (GRP78), GRP78 protein, Heat-Shock Proteins - metabolism, Homeostasis - drug effects, Humans, Immunity, immunogenic cell death, Immunogenic Cell Death - drug effects, Immunogenicity, Lymphocytes, Lymphocytes T, Lymphocytes, Tumor-Infiltrating - drug effects, Lymphocytes, Tumor-Infiltrating - immunology, Male, Membrane Proteins - metabolism, Metastases, Mice, Mice, Inbred BALB C, Mitochondria, Mitochondrial Proteins - metabolism, Models, Biological, Mortality, Multivariate Analysis, Oxaliplatin - pharmacology, Oxaliplatin - therapeutic use, Protein Binding - drug effects, Protein folding, Protein Stability - drug effects, Proteins, Regrowth, Stress, Survival, T-Lymphocytes - drug effects, T-Lymphocytes - immunology