Functional role of PLK1 in colorectal cancer progression and its potential to chemoresistance

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.