Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers

Abstract

Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with>4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival ( < 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer.

Gene expression profile of lipopolysaccharide‑induced apoptosis of nucleus pulposus cells reversed by syringic acid

“…in neuroblastoma cells, downregulation of PlK4 could also dramatically increase the rate of apoptosis and lead to an inhibition of cell migratory and invasive abilities (28). additionally, apoptotic death occurred in lung cancer cells after treatment with cFi-400945, a PlK4 inhibitor (29). in the present study, the expression of PlK4 was downregulated in lPS-induced apoptosis and reversed by Syra treatment.…”

High PLK4 expression promotes tumor progression and induces epithelial‑mesenchymal transition by regulating the Wnt/β‑catenin signaling pathway in colorectal cancer Corrigendum in /10.3892/ijo.2021.5213

“…In addition, the oncogenic role of PLK4 has been studied in various types of cancer ( 9 - 15 ). The expression of PLK4 has been detected in breast cancer ( 11 , 14 ), lung cancer ( 12 ), neuroblastoma ( 13 ) and prostate cancer ( 15 ); however, its expression pattern differs among various types of cancer. Increased PLK4 expression is correlated with higher rates of metastasis in breast cancer ( 11 , 14 ).…”

Polo‐like kinase 4 correlates with greater tumor size, lymph node metastasis and confers poor survival in non‐small cell lung cancer

“…Thus, PLK4 high expression was correlated with unfavorable clinicopathological features in NSCLC patients. Besides, inhibition of PLK4 was previously shown to cause defects in cell mitosis and induce cell death in NSCLC cells via regulating centriole duplication, which implied that PLK4 suppressed cell apoptosis and contributed to tumor growth in NSCLC . Thus, PLK4 was associated with greater tumor size and higher TNM stage in NSCLC patients.…”

“…In clinical studies, PLK4 is shown to be associated with higher pathological grade and poor prognosis in glioblastoma patients . As for in lung cancer, PLK4 inhibitor attenuated tumor growth via deregulating centriole duplication, mitotic defects, and deaths of lung cancer cells . Whereas for NSCLC, to be specific, the correlation of PLK4 with tumor development, progression, or prognosis is still unclear.…”