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Decoding molecular interplay between RUNX1 and FOXO3a underlying the pulsatile IGF1R expression during acquirement of chemoresistance.
- Source :
-
BBA: Molecular Basis of Disease . Jun2020, Vol. 1866 Issue 6, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
-
Abstract
- Hyperactive Insulin like growth factor-1-receptor (IGF1R) signalling is associated with development of therapy resistance in many cancers. We recently reported a pulsatile nature of IGF1R during acquirement of platinum-taxol resistance in Epithelial Ovarian Cancer (EOC) cells and a therapy induced upregulation in IGF1R expression in tumors of a small cohort of high grade serous EOC patients. Here, we report Runt-related transcription factor 1 (RUNX1) as a novel transcriptional regulator which along with another known regulator Forkhead Box O3 (FOXO3a), drives the dynamic modulation of IGF1R expression during platinum-taxol resistance development in EOC cells. RUNX1-FOXO3a cooperatively bind to IGF1R promoter and produce a transcriptional surge during onset of resistance and such co-operativity falls apart when cells attain maximal resistance resulting in decreased IGF1R expression. The intriguing descending trend in IGF1R and FOXO3a expressions is caused by a Protein Kinase B (AKT)-FOXO3a negative feedback loop exclusively present in the highly resistant cells eliciting the pulsatile behaviour of IGF1R and FOXO3a. In vivo molecular imaging revealed that RUNX1 inhibition causes significant attenuation of the IGF1R promoter activity, decreased tumorigenicity and enhanced drug sensitivity of tumors of early resistant cells. Altogether our findings delineate a dynamic interplay between several molecular regulators driving pulsatile IGF1R expression and identify a new avenue for targeting EOC through RUNX1-IGF1R axis during acquirement of chemoresistance. Unlabelled Image • RUNX1 is a novel regulator of IGF1R during chemoresistance development in EOC cells. • RUNX1 modulates FOXO3a mediated transcriptional surge in IGF1R at onset of resistance. • An active AKT-FOXO3a negative feedback loop leads to pulsatile dynamics of IGF1R. • RUNX1 inhibition in combination with platinum-taxol reverses resistance in EOC cells. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09254439
- Volume :
- 1866
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- BBA: Molecular Basis of Disease
- Publication Type :
- Academic Journal
- Accession number :
- 142537261
- Full Text :
- https://doi.org/10.1016/j.bbadis.2020.165754