RT Journal Article
SR Electronic
T1 CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 843995
DO 10.1101/843995
A1 Mushtaq Ahmed Nengroo
A1 Shrankhla Maheshwari
A1 Akhilesh Singh
A1 Anup Kumar Singh
A1 Rakesh Kumar Arya
A1 Priyank Chaturvedi
A1 Ayushi Verma
A1 Krishan Kumar Saini
A1 Annapurna Gupta
A1 Anjali Mishra
A1 Dipak Datta
YR 2019
UL http://biorxiv.org/content/early/2019/11/15/843995.abstract
AB CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, CXCR4 signaling inhibitor drug Plerixafor has shown limited clinical success in cancer treatment. Therefore, CXCR4 signaling may not be the exclusive contributor to its pro-tumorigenic functions. In our continuous effort to understand the chemokine receptor signaling inhibition as cancer therapy, here we unexpectedly discovered that instead of its signaling, intracellular CXCR4 protein augments therapy resistance and pro-tumorigenic functions. Unbiased proteome profiler apoptosis array followed by immunoblot, FACS, real-time PCR and ChIP analyses demonstrate that CXCR4 promotes DR5 downregulation via modulating differential recruitment of transcription factors p53 and YY1 to its promoter. Surprisingly, inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, its loss compromised colon tumor growth in vivo. Finally, TCGA data mining and human patient sample data analysis showed CXCR4 and DR5 are inversely regulated in human cancers. Together, we showed evidence for the first time that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.