PO.ET09.04 · 实验与分子治疗
PLK1在结直肠癌进展中的功能作用及其对化疗耐药的潜在影响
Functional role of PLK1 in colorectal cancer progression and its potential to chemoresistance
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的
结直肠癌是全球患病率和死亡率均较高的癌症，根据分期采用手术、化疗和放疗进行治疗。晚期结直肠癌大多可通过手术切除治愈，而手术联合化疗仍是大多数晚期结直肠癌患者的主要治疗方法。耐药性是结直肠癌治疗的主要障碍之一，凸显了对新治疗靶点的需求。Polo样激酶1（PLK1）是细胞周期的关键调节因子，在结直肠癌以及多种恶性肿瘤中频繁过表达，并与不良预后相关。为探索结直肠癌化疗耐药的机制并确定克服耐药的潜在策略，我们研究了PLK1的功能作用及其对药物敏感性的影响。
方法
使用siRNA沉默PLK1，并开展评估增殖、迁移、侵袭和划痕愈合的功能研究，以探究其在结直肠癌中的作用。为评估化疗耐药，用oxaliplatin处理结直肠癌细胞。此外，我们评估了oxaliplatin与PLK1-PROTAC+oxaliplatin的药物敏感性，以评价其对细胞存活的影响。在BALB/c裸鼠中皮下植入CRC细胞系来源的肿瘤，以评估药物处理后的肿瘤生长。
结果
抑制PLK1表达显著损害了结直肠癌的功能。PLK1低表达的结直肠癌细胞对oxaliplatin的敏感性显著增加。与单用oxaliplatin相比，PLK1靶向PROTAC与oxaliplatin联合处理显著降低了结直肠癌细胞的活力。在体内研究中，与oxaliplatin相比，PLK1-PROTAC对肿瘤生长的抑制作用显著增强。
结论
抑制PLK1表达导致结直肠癌细胞功能显著下降，凸显了其在维持肿瘤生长和转移功能中的重要作用。这些发现提示PLK1可能作为抑制结直肠癌进展和克服化疗耐药的潜在治疗靶点。
查看英文原文 English abstract
OBJECTIVE
Colorectal cancer is a cancer with high prevalence and mortality rates worldwide, treated with surgery, chemotherapy, and radiation therapy depending on the stage. Advanced colorectal cancer is mostly curable by surgical excision combined with chemotherapy remains the primary treatment for most patients with advanced colorectal cancer. Drug resistance is one of the major obstacles in colorectal cancer treatment, highlighting the need for new therapeutic targets. Polo-like kinase 1(PLK1), a key regulator of the cell cycle, is frequently overexpressed in colorectal cancer as well as various malignancies and associated with poor prognosis. To explore the mechanisms of chemoresistance in colorectal cancer and identify potential strategies to overcome it, we investigated the functional role of PLK1 and its impact on drug sensitivity.
METHODS
PLK1 was silenced using siRNA, and functional studies assessing proliferation, migration, invasion, and wound healing were conducted to investigate its role in colorectal cancer. To evaluate chemoresistance, colorectal cancer cells were treated with oxaliplatin. Additionally, we assessed the drug sensitivity of the oxaliplatin versus PLK1-PROTAC+oxaliplatin to evaluate its impact on cell survival. Subcutaneous implantation of CRC cell line-derived tumors was performed in BALB/c nude mice to assess tumor growth after drug treatment.
RESULTS
Suppression of PLK1 expression significantly impaired function of colorectal cancer. Colorectal cancer cells with low PLK1 expression exhibited significantly increased sensitivity to oxaliplatin. Compared to oxaliplatin alone, treatment with a PLK1-targeting PROTAC in combination with oxaliplatin significantly reduced colorectal cancer cell viability. In the in vivo study, PLK1-PROTAC exerted significantly enhanced suppression of tumor growth compared with Oxaliplatin.
CONCLUSION
Suppression of PLK1 expression led to a significant decrease in colorectal cancer cell function highlighting its essential role in sustaining tumor growth and metastatic functions. These findings suggest that PLK1 may serve as a potential therapeutic target for inhibiting colorectal cancer progression and overcoming chemoresistance.
利益披露 Disclosure
J. Bang, None..
S. Jeon, None.