Abstract
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.
Highlights
Ovarian cancer is the deadliest gynecological cancer and the fifth leading cause of cancer-related deaths in women in the U.S [1]
High expression of CXCR2 or its ligand CXCL1 leads to increased ovarian cancer proliferation, which is believed to be partly mediated by transactivation of EGFR signaling, and the suppression of CXCR2 leads to apoptosis [16, 17]
Since Akt signaling was involved in CXCR2-mediated p21 downregulation in p53WT cells, we investigated whether CXCR2 could regulate p21 in p53-null cells in a similar way
Summary
Ovarian cancer is the deadliest gynecological cancer and the fifth leading cause of cancer-related deaths in women in the U.S [1]. Type I tumors include low-grade, mucinous, endometrioid and clear cells, in which the lesion is fully characterized, leading to a better prognosis. Increasing evidence has implicated a high expression of CXCR2 in advanced stage of ovarian carcinomas leading to increased cancer progression and enhanced angiogenesis [16]. High expression of CXCR2 or its ligand CXCL1 leads to increased ovarian cancer proliferation, which is believed to be partly mediated by transactivation of EGFR signaling, and the suppression of CXCR2 leads to apoptosis [16, 17]. In addition to clear evidence of a role for CXCR2 in cancer progression, CXCR2 is known to influence oncogene-induced and replicative senescence through a DNA-damage [18]. Our previous study confirmed the role of NF-κB signaling through EGFR-transactivated Akt on the CXCR2-driven ovarian cancer progression [19, 20]. CXCR2 regulates cell cycle through multiple signaling pathways, the mechanistic effects of CXCR2 on ovarian cancer cell proliferation is poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
