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.

中文翻译：

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ATAD3A 稳定 GRP78 以抑制结直肠癌获得性化疗耐药的 ER 应激


含有 AAA 结构域的 3A (ATAD3A) 是一种核编码的线粒体蛋白，在内质网 (ER) 和线粒体之间的通讯中发挥重要作用，参与癌症转移。在这里，我们发现 ATAD3A 表达升高在临床上与结直肠癌 (CRC) 患者，特别是接受辅助化疗的高危 CRC 患者较差的 5 年无病生存率相关。我们的结果表明 ATAD3A 显着上调，可减少化疗诱导的癌细胞死亡。我们通过 RNA 测序 (RNA-seq) 发现，ATAD3A 的敲低会导致蛋白质加工失调，从而诱导 ER 应激。为了应对化疗引起的 ER 应激，ATAD3A 与升高的 GRP78 蛋白相互作用，协助蛋白折叠并减轻 ER 应激，从而促进癌细胞存活。内质网应激的减少导致钙网蛋白的表面暴露减少，钙网蛋白是免疫原性细胞死亡和抗肿瘤免疫的引发剂。然而，ATAD3A 的沉默会增强细胞死亡，触发化疗诱导的 ER 应激抗肿瘤免疫的可行性，增加 T 淋巴细胞的浸润并延迟体外和体内肿瘤的再生。临床上，ATAD3A较少的CRC患者具有高密度的CD45 ⁺瘤内浸润淋巴细胞(TIL)和记忆CD45RO ⁺ TIL。综上所述，我们的结果表明，针对 ATAD3A 的药物靶向可能是增强接受辅助化疗的 CRC 患者抗肿瘤免疫力的潜在治疗策略。