Abstract 6325: CXCR4 intracellular protein regulates chemotherapy resistance by modulating the expression of death receptor 5

Abstract

Abstract Chemotherapy resistance is one of the pivotal reasons for cancer-associated huge mortality and morbidity. Cancer cells become therapy resistant by smartly evading the execution of apoptosis. Death Receptors (DR) are critical pro-apoptotic factors that regulate cell death, and paucity of death receptors in cancer cells promotes therapy resistance. High expression of CXCR4 is strongly correlated with poor prognosis and adverse clinical outcomes. Inhibitors of the CXCL12-CXCR4 axis, such as FDA approved drug plerixafor (AMD3100), and Nox-A12 have shown limited clinical success in cancer treatment. Alternately, CXCR7, another CXCL12 binding receptor, could be the reason for the limited success of the CXCR4 blockade in clinics. However, recent preclinical data for blocking both the chemokine receptors failed to explain the pro-tumorigenic functions of these axes. Therefore, CXCR4-CXCL12 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 CXCR4-CXCL12 signaling, CXCR4 intracellular protein augments therapy resistance and pro-tumorigenic functions. By utilizing stable gain and loss of function approaches, we observed that CXCR4 selectively resists and sensitizes cancer cells against paclitaxel therapy. Our unbiased apoptosis array followed by immunoblot, FACS, real-time PCR, and ChIP analysis clearly demonstrate that CXCR4 promotes downregulation of pro-apoptotic protein DR5 via modulating differential recruitment of transcription factors p53 and YY1 to the promoter of DR5 gene. Inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, three different colon cancer xenograft models evidently exhibited loss of CXCR4 protein results in compromised colon tumor growth in vivo. Finally, performing TCGA data mining, real-time PCR, immunofluorescence microscopy of human cancer patient samples and cell lines, we observed that expression of CXCR4 and DR5 are inversely correlated in human cancer. Together, we showed for the first time that targeting intracellular CXCR4 protein may be critical to dampen the pro-tumorigenic functions of CXCR4. Citation Format: Mushtaq Ahmad Nengroo, Shrankhla Maheshwari, Akhilesh Singh, Anup Kumar Singh, Priyank Chaturvedi, Ayushi Verma, Rakesh Kumar Arya, Krishan Kumar Saini, Annapurna Gupta, Anjali Mishra, Dipak Datta. CXCR4 intracellular protein regulates chemotherapy resistance by modulating the expression of death receptor 5 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6325.