CXCR4 intracellular protein promotes drug resistance and tumorigenic potential by inversely regulating the expression of Death Receptor 5

Author:

Nengroo Mushtaq A.,Maheshwari Shrankhla,Singh Akhilesh,Verma Ayushi,Arya Rakesh K.,Chaturvedi Priyank,Saini Krishan K.,Singh Anup K.,Sinha Abhipsa,Meena Sanjeev,Gupta Annapurna,Mishra Anjali,Sarkar Jayanta,Datta DipakORCID

Abstract

AbstractChemokine receptor CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, blockade of CXCL12-CXCR4 signaling axis by inhibitors like Nox-A12, FDA approved CXCR4 inhibitor drug AMD3100 have shown limited clinical success in cancer treatment. Therefore, exclusive contribution of CXCR4-CXCL12 signaling in pro-tumorigenic function is questionable. In our pursuit to understand the impact of chemokine signaling in carcinogenesis, we reveal that instead of CXCR4-CXCL12 signaling, presence of CXCR4 intracellular protein augments paclitaxel resistance and pro-tumorigenic functions. In search of pro-apoptotic mechanisms for CXCR4 mediated drug resistance; we discover that DR5 is a new selective target of CXCR4 in breast and colon cancer. Further, we detect that CXCR4 directs the differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 in course of its transcriptional repression. Remarkably, inhibiting CXCR4-ligand-mediated signals completely fails to block the above phenotype. Overexpression of different mutant versions of CXCR4 lacking signal transduction capabilities also result in marked downregulation of DR5 expression in colon cancer indeed confirms the reverse relationship between DR5 and intracellular CXCR4 protein expression. Irrespective of CXCR4 surface expression, by utilizing stable gain and loss of function approaches, we observe that intracellular CXCR4 protein selectively resists and sensitizes colon cancer cells against paclitaxel therapy in vitro and in vivo. Finally, performing TCGA data mining and using human breast cancer patient samples, we demonstrate that expression of CXCR4 and DR5 are inversely regulated. Together, our data suggest that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4.

Funder

CSIR | Central Drug Research Institute

CSIR Fellowship Grant

DST NPDF Grant

UGC Fellowship Grant

Indian Council of Medical Research

SGPGI Institutional Fund

DST | Science and Engineering Research Board

Department of Biotechnology, Ministry of Science and Technology

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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