Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
Neoplasma. 2023 Apr;70(2):272-286. doi: 10.4149/neo_2023_221107N1088.
Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.
核普遍存在的酪蛋白和细胞周期依赖性激酶底物 1（NUCKS1）在多种恶性肿瘤中高度表达，并且作为癌基因发挥作用；然而，其在结直肠癌（CRC）中的作用尚不清楚。我们旨在探索 NUCKS1 的功能和调节机制，以及针对 CRC 中 NUCKS1 的潜在治疗剂。我们在 CRC 细胞中敲低和过表达 NUCKS1，并在体外和体内探索其作用。进行流式细胞术、CCK-8、Western blot、集落形成、免疫组织化学、体内致瘤和透射电子显微镜分析，以确定 NUCKS1 对 CRC 细胞功能的影响。使用 LY294002 检查 NUCKS1 在 CRC 细胞中的表达机制。使用 CTRP 和 PRISM 数据集分析 NUCKS1 高表达的 CRC 患者的潜在治疗剂，并通过 CCK-8 和 Western blot 确定选定药物的功能。我们揭示 NUCKS1 在 CRC 组织中高度表达，并且与 CRC 患者的预后不良相关。NUCKS1 敲低诱导细胞周期停滞，抑制 CRC 细胞增殖，并促进细胞凋亡和自噬。当 NUCKS1 过表达时，这些结果被逆转。从机制上讲，NUCKS1 通过激活 PI3K/AKT/mTOR 信号通路发挥致癌作用。当使用 LY294002 抑制 PI3K/AKT 通路时，这种作用被逆转。此外，我们确定米托蒽醌在 NUCKS1 过表达的 CRC 细胞中表现出高药物敏感性。这项工作表明，NUCKS1 通过 PI3K/AKT/mTOR 信号通路在 CRC 进展中发挥关键作用。此外，米托蒽醌可能是 CRC 治疗的潜在治疗剂。因此，NUCKS1 代表了一种有前途的抗肿瘤治疗靶点。
