Ignacio Rosa Mistica C, Dong Yuan-Lin, Kabir Syeda M, Choi Hyeongjwa, Lee Eun-Sook, Wilson Andrew J, Beeghly-Fadiel Alicia, Whalen Margaret M, Son Deok-Soo
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, USA.
Oncotarget. 2018 Jan 15;9(11):9751-9765. doi: 10.18632/oncotarget.24231. eCollection 2018 Feb 9.
Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner.
卵巢癌（OC）在妇科恶性肿瘤中死亡率最高。OC中的趋化因子受体CXCR2与不良预后相关。然而，CXCR2调节OC增殖的机制仍知之甚少。我们从亲本p53野生型（WT）、突变型和缺失型OC细胞中生成了CXCR2阳性细胞，并以p53依赖和非依赖的方式评估了CXCR2对OC细胞增殖的作用。CXCR2促进细胞生长速率：p53WT>突变型=缺失型细胞。Nutlin-3是一种p53稳定剂，可抑制p53WT细胞中的细胞增殖，但对p53突变型或缺失型细胞几乎没有影响，表明CXCR2介导的增殖具有p53依赖性。CXCR2降低了p21的调节因子p53蛋白，并且仅在p53WT细胞中下调了p21启动子活性。p21启动子的p53反应元件（RE）在这种CXCR2介导的p21下调中起关键作用。此外，CXCR2阳性细胞比CXCR2阴性细胞激活更多的Akt，随后小鼠双微体（Mdm2）增强。沉默Mdm2或Akt1会上调p21表达，而Akt1过表达会在p53WT细胞的启动子和蛋白水平上下调p21。细胞周期分析显示，CXCR2在p53缺失型细胞中降低了p21基因。有趣的是，罗米地辛（组蛋白脱乙酰酶抑制剂）诱导的p21上调在p53缺失型细胞的p21启动子中不涉及p53 RE。罗米地辛降低了Akt1和Mdm2的蛋白水平，导致p53缺失型细胞中p21的诱导。CXCR2通过激活Akt诱导的Mdm2降低了罗米地辛诱导的p21上调。综上所述，CXCR2通过Akt-Mdm2信号通路以p53依赖和非依赖的方式抑制p21来增强细胞增殖。
