Induction of centrosome amplification and chromosome instability in p53-null cells by transient exposure to subtoxic levels of S-phase-targeting anticancer drugs

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Abstract
Chromosome instability (CIN) is one of the most important phenotypes in tumor progression, introducing multiple mutations required for acquisition of further malignant characteristics. Abnormal amplification of centrosomes, which is frequently observed in human cancer, has been shown to contribute to CIN by increasing the frequency of mitotic defects. Here, we show that transient exposure to subtoxic concentrations of commonly used anticancer drugs that target DNA synthesis induces centrosome amplification in cells lacking p53 tumor suppressor protein, by allowing continuous centrosome duplication in the absence of DNA synthesis. When these cells are released from cell cycle arrest by removal of drugs, cells suffer extensive destabilization of chromosomes. Considering that p53 is the most frequently mutated gene in human cancer and that CIN is known to be associated with acquisition of malignant phenotypes, our observations may explain why recurrent tumors, after chemotherapy, often exhibit more malignant characteristics than the original tumors. The tumor cells that are exposed to subtoxic levels of DNA synthesis-targeting drugs will be arrested and undergo centrosome amplification. Upon cessation of chemotherapy, these cells will re-enter cell cycling, and experience extensive CIN due to the presence of amplified centrosomes. This in turn promotes generation of tumor cells equipped with further malignant characteristics.