Molecular Mechanism Of Nuclear Exported NAC1-contributed Docetaxel Resistance And Its Impact In Cancer Treatment

Objective:To study the molecular mechanism of nuclear exported NAC1 in contributing docetaxel resistance and the impact of its intervention on cancer treatment.Methods:In this study,we investigated regulatory mechanism controling NAC1 nuclear-cytoplasmic shuttling,the molecular mechanism underlying how nuclear exported NAC1 contributes todocetaxel resistance and further explored the potential of nuclear exported NAC1 as a novel target for cancer treatment.Molecular biology,cell biology,pharmacology approaches and other methods were used in this study.Results:We demonstrated:1)NAC1 has a nuclear export signal(NES)at the N terminus(aa 17-28)that contributes to NACI nuclear-cytoplasmic shuttling when subjected to doxcetaxel treatment;2)molecular interaction between NAC1 and Cullin3 and demonstrated Cullin3 interacts with RGS2,a tumor suppressor,through NAC1,to ubiquitinate and degrade RGS2 in tumor cells,which contributes to doxcetaxel resistance;3)The membrane permeable polypeptide targeting chromosomal maintenance(CRM1)of NAC1 would interfere with the degradation of RGS2 and restoring the sensitivity of cancer cells to doxcetaxel.Conclusion:The effect of cytoplasmic NAC1 on doxcetaxel resistance is mediated through CUL3-NAC1-RGS2 pathway.These findings reveal novel cellular functions of NAC1 in therapy resistance,and provide an evidence for nuclear exported NAC1 as a novel target for cancer treatment.