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ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2021 Sep; Vol. 236 (9), pp. 6481-6495. Date of Electronic Publication: 2021 Feb 12. - Publication Year :
- 2021
-
Abstract
- 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 <superscript>+</superscript> intratumoral infiltrating lymphocytes (TILs) and memory CD45RO <superscript>+</superscript> 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.<br /> (© 2021 Wiley Periodicals LLC.)
- Subjects :
- Aged
Animals
Cell Line, Tumor
Colorectal Neoplasms drug therapy
Colorectal Neoplasms immunology
Disease-Free Survival
Endoplasmic Reticulum Chaperone BiP
Female
Homeostasis drug effects
Humans
Immunogenic Cell Death drug effects
Lymphocytes, Tumor-Infiltrating drug effects
Lymphocytes, Tumor-Infiltrating immunology
Male
Mice, Inbred BALB C
Models, Biological
Multivariate Analysis
Oxaliplatin pharmacology
Oxaliplatin therapeutic use
Protein Binding drug effects
Protein Stability drug effects
T-Lymphocytes drug effects
T-Lymphocytes immunology
Mice
ATPases Associated with Diverse Cellular Activities metabolism
Colorectal Neoplasms metabolism
Colorectal Neoplasms pathology
Drug Resistance, Neoplasm drug effects
Endoplasmic Reticulum Stress drug effects
Heat-Shock Proteins metabolism
Membrane Proteins metabolism
Mitochondrial Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4652
- Volume :
- 236
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 33580514
- Full Text :
- https://doi.org/10.1002/jcp.30323