ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer.
J Cell Physiol
; 236(9): 6481-6495, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-33580514
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+ 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Resistencia a Antineoplásicos
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Proteínas Mitocondriales
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Estrés del Retículo Endoplásmico
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ATPasas Asociadas con Actividades Celulares Diversas
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Proteínas de Choque Térmico
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Límite:
Aged
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Cell Physiol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Taiwán