Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow, 226031, India.
Academy of Scientific and Innovative Research, New Delhi, India.
Cell Death Dis. 2021 May 8;12(5):464. doi: 10.1038/s41419-021-03730-8.
Chemokine 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.
趋化因子受体 CXCR4 在实体肿瘤中的过度表达与不良预后和临床结局不良密切相关。然而，抑制剂如 Nox-A12、已获 FDA 批准的 CXCR4 抑制剂 AMD3100 阻断 CXCL12-CXCR4 信号轴在癌症治疗中的临床疗效有限。因此，CXCR4-CXCL12 信号在促进肿瘤发生功能中的独特作用是值得怀疑的。在我们追求了解趋化因子信号在致癌作用中的影响时，我们发现，代替 CXCR4-CXCL12 信号，CXCR4 细胞内蛋白的存在增强了紫杉醇耐药性和促进肿瘤发生的功能。在寻找 CXCR4 介导的耐药性的促凋亡机制时；我们发现 DR5 是乳腺癌和结肠癌中 CXCR4 的一个新的选择性靶标。此外，我们发现 CXCR4 指导转录因子 p53 和 YY1 在其转录抑制过程中向 DR5 启动子的差异募集。值得注意的是，抑制 CXCR4-配体介导的信号完全不能阻断上述表型。表达不同缺乏信号转导能力的 CXCR4 突变体版本也导致结肠癌中 DR5 表达的显著下调，这确实证实了 DR5 与细胞内 CXCR4 蛋白表达之间的反向关系。无论 CXCR4 表面表达如何，通过利用稳定的获得和丧失功能方法，我们观察到细胞内 CXCR4 蛋白选择性地抵抗和敏化结肠癌细胞对紫杉醇治疗的体外和体内。最后，进行 TCGA 数据挖掘并使用人类乳腺癌患者样本，我们证明了 CXCR4 和 DR5 的表达呈负相关。总之，我们的数据表明，靶向 CXCR4 细胞内蛋白可能是抑制 CXCR4 促进肿瘤发生功能的关键。
