Abstract
Wild-type p53 is a stress-responsive transcription factor and potent tumor suppressor. P53 activates or represses genes involved in cell cycle progression or apoptosis in order to arrest the cell cycle or induce cell death. Transcription repression by p53 is indirect and requires repressive members of the RB-family (RB1, RBL1, RBL2) and formation of repressor complexes of RB1-E2F and RBL1/RBL2-DREAM. Many aurora kinase A/B (AURKA/B) pathway genes are repressed in a p53-DREAM-dependent manner. We found heightened expression of RBL2 and reduced expression of AURKA/B pathway genes is associated with improved outcomes in p53 wild-type but not p53 mutant non-small cell lung cancer (NSCLC) patients. Knockdown of p53, RBL2, or the DREAM component LIN37 increased AURKA/B pathway gene expression and reduced paclitaxel and radiation toxicity in NSCLC cells. In contrast, pharmacologic inhibition of AURKA/B or knockdown of AURKA/B pathway components increased paclitaxel and IR sensitivity. The results support a model in which p53-RBL2-DREAM-mediated repression of the AURKA/B pathway contributes to tumor suppression, improved tumor therapy responses, and better outcomes in p53 wild-type NSCLCs.
Highlights
Wild-type p53 is a stress-responsive transcription factor and potent tumor suppressor
RBL2 negatively correlates with DREAM target gene expression in WT p53 non-small cell lung cancer (NSCLC) patients
The results suggest that p53 status influences the expression correlation between RBL2 and a substantial subset of DREAM-regulated genes. 22 genes from this 140 gene set are in the aurora kinase A/B (AURKA/B) pathway (Table 1)[37,38]
Summary
Wild-type p53 is a stress-responsive transcription factor and potent tumor suppressor. We found heightened expression of RBL2 and reduced expression of AURKA/B pathway genes is associated with improved outcomes in p53 wild-type but not p53 mutant non-small cell lung cancer (NSCLC) patients. Knockdown of p53, RBL2, or the DREAM component LIN37 increased AURKA/B pathway gene expression and reduced paclitaxel and radiation toxicity in NSCLC cells. The results support a model in which p53-RBL2-DREAMmediated repression of the AURKA/B pathway contributes to tumor suppression, improved tumor therapy responses, and better outcomes in p53 wild-type NSCLCs. The tumor suppressor protein p53 is a stress-responsive transcription factor and key determinant of cancer therapy responses[1–8]. AURKA/B phosphorylate G2/M phase substrates to affect different steps in mitosis, including mitotic spindle assembly, centrosome separation, and others Both AURKA and B have oncogenic activity, and their high expression is associated with worse. AURKA/B inhibitors (e.g. Alisertib) are currently in combination clinical trials in breast cancer, head and neck cancer, advanced lung cancer, and others
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