SB225002 promotes mitotic catastrophe in chemo-sensitive and -resistant ovarian cancer cells independent of p53 status in vitro.

Abstract

Recent evidence indicates that CXCR2 signaling is crucial for cancer progression, and its antagonist SB225002 induces apoptosis in Wilms' tumor cells. Here, we investigated the effect of SB225002 on cell cycle progression and apoptosis induction in vitro, using CDDP-sensitive and -resistant OVCA cell lines with different p53 status (wild type, mutant or null). Adenovirus infection of wild-type p53 or transfection of p53 siRNA was used to over-express or knock-down p53. Cell cycle and apoptosis were determined by flow cytometry or Hoechst staining and observation of nuclear morphology. Our data demonstrated that SB225002 induced apoptosis in both wild-type and p53-deficient ovarian cancer (OVCA) cells through alternative mechanisms. SB225002 promoted mitotic catastrophe, as evidenced by the accumulation of mitotic cells with spindle abnormalities, chromosome mis-segregation, multi-polar cell division, multiple nuclei, aneuploidy/polyploidy and subsequent extensive apoptosis. SB225002-induced mitotic catastrophe appeared to be mediated by down-regulation of checkpoint kinase Chk1 and Cdk1-cyclin B activation. In cells expressing wild-type p53 (OV2008 and C13*), SB225002 increased total and phospho-Ser p53 levels, and p53 knock-down decreased SB225002-induced apoptosis, without affecting premature mitosis. These results suggest that SB225002 induces p53-dependent apoptosis, and provokes mitotic catastrophe in p53-independent manner in p53 wild-type cells. Reconstitution with wild-type P53 in P53-null SKOV3 cell attenuated SB225002-induced mitotic catastrophe, suggesting p53 prevented mitotic catastrophe induced by SB225002 in p53-deficient OVCA cells. Finally, the effect of SB225002 could not be prevented by pretreatment with CXCR2 ligand or its neutralizing antibody. The present studies demonstrate for the first time that SB225002 has dual actions in OVCA cells, inducing classic apoptosis through p53 activation and provoking mitotic catastrophe in both p53 wild-type and deficient cells by Chk1 inhibition and Cdk activation. These findings raise the possibility of SB225002 as a new candidate molecule for OVCA therapy independent of the p53 status.

• Authors: Meirong Du, Qing Qiu, Andree Gruslin, John Gordon, Miao He, Chi Chung Chan, Dajin Li, Benjamin K Tsang
• Journal: PloS one (PLoS One) Vol. 8 Issue 1 Pg. e54572 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23359652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CXCL1 protein, human
• Chemokine CXCL1
• DNA Primers
• DNA, Complementary
• Interleukin-8
• Phenylurea Compounds
• Receptors, Interleukin-8B
• SB 225002
• Tumor Suppressor Protein p53

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Base Sequence
• Cell Line, Tumor
• Chemokine CXCL1 (metabolism)
• DNA Damage
• DNA Primers
• DNA, Complementary
• Drug Resistance, Neoplasm
• Female
• Humans
• Interleukin-8 (metabolism)
• Mitosis (drug effects)
• Ovarian Neoplasms (metabolism, pathology)
• Phenylurea Compounds (pharmacology)
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-8B (metabolism)
• Tumor Suppressor Protein p53 (metabolism)