Abstract：
Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.
摘要：
胰腺导管腺癌(PDAC),以异质性肿瘤微环境和基因突变为特征，传达了令人沮丧的预后和对化疗和免疫疗法的低反应。这里,我们发现检查点抑制因子1(CHES1)在PDAC中充当肿瘤抑制因子,并与患者预后相关.功能实验表明，CHES1通过调节细胞衰老抑制PDAC的增殖和侵袭。为了进一步确定PDAC中CHES1的下游因素，进行了无标记定量蛋白质组学分析，这表明致癌醛酮还原酶1B10（AKR1B10）在PDAC中被CHES1转录抑制。AKR1B10促进PDAC细胞的恶性活性和抑制衰老表型。此外，用齐墩果酸（OA）药物抑制AKR1B10显着诱导肿瘤消退和PDAC细胞对吉西他滨的敏感性，这种联合疗法没有引起明显的副作用。获救的实验表明，CHES1通过AKR1B10介导的PDAC衰老调节肿瘤发生和吉西他滨敏感性。总之,这项研究表明，CHES1/AKR1B10轴调节PDAC的进展和细胞衰老，这可能为PDAC的药物靶向和衰老诱导疗法提供收入。
