PT  - JOURNAL ARTICLE
AU  - Mushtaq Ahmed Nengroo
AU  - Shrankhla Maheshwari
AU  - Akhilesh Singh
AU  - Anup Kumar Singh
AU  - Rakesh Kumar Arya
AU  - Priyank Chaturvedi
AU  - Ayushi Verma
AU  - Krishan Kumar Saini
AU  - Annapurna Gupta
AU  - Anjali Mishra
AU  - Dipak Datta
TI  - CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5
AID  - 10.1101/843995
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 843995
4099  - http://biorxiv.org/content/early/2019/11/15/843995.short
4100  - http://biorxiv.org/content/early/2019/11/15/843995.full
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.