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Targeting PLK1 as a novel chemopreventive approach to eradicate preneoplastic mucosal changes in the head and neck
D Vicky de Boer1, Sanne R Martens-de Kemp1, Marijke Buijze1
1Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Abstract:
Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, are frequently dysplastic and occasionally macroscopically visible. Currently, no adequate treatment options exist to prevent tumor development. Array-based screening with a panel of tumor-lethal small interfering RNAs (siRNAs) identified Polo-like kinase 1 (PLK1) as essential for survival of preneoplastic cells. Inhibition of PLK1 caused cell death of preneoplastic and HNSCC cells, while primary cells were hardly affected. Both siRNAs and small molecule inhibitors caused a strong G2/M cell cycle arrest accompanied by formation of monopolar spindles. In a xenografted mouse model PLK1 caused a significant tumor growth delay and cures, while chemoradiation had no effect. Thus, PLK1 seems to be a promising target for chemopreventive treatment of preneoplastic cells, and could be applied to prevent HNSCC and local relapses.
Insights
Targeting Polo-like kinase 1 (PLK1) effectively eliminates preneoplastic cells and head and neck squamous cell carcinoma (HNSCC) cells, offering a potential strategy for preventing HNSCC development and recurrence.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Head and neck squamous cell carcinomas (HNSCC) arise from preneoplastic fields in the upper aerodigestive tract.
- These preneoplastic fields exhibit genetic alterations and dysplasia, with limited preventive treatment options.
- Current therapeutic strategies lack efficacy in preventing tumor development in these fields.
Purpose of the Study:
- To identify novel therapeutic targets for the prevention of HNSCC and its local relapses.
- To investigate the role of Polo-like kinase 1 (PLK1) in the survival of preneoplastic and HNSCC cells.
Main Methods:
- Array-based screening using a panel of tumor-lethal small interfering RNAs (siRNAs).
- Inhibition of PLK1 using siRNAs and small molecule inhibitors.
- Assessment of cell cycle progression and spindle formation.
- Evaluation in a xenografted mouse model.
Main Results:
- PLK1 was identified as essential for the survival of preneoplastic and HNSCC cells.
- PLK1 inhibition led to cell death in preneoplastic and HNSCC cells, with minimal impact on primary cells.
- PLK1 inhibition induced G2/M cell cycle arrest and monopolar spindle formation.
- PLK1 inhibition significantly delayed tumor growth and achieved cures in a mouse model, outperforming chemoradiation.
Conclusions:
- PLK1 is a promising molecular target for the chemoprevention of preneoplastic lesions.
- Targeting PLK1 offers a potential strategy to prevent the development of HNSCC and local relapses.
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