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CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NF-?B activation via EGFR-transactivated Akt signaling.

ABSTRACT: Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-?B (NF-?B) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of I?B. CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation. CXCR2 positive cells also activated more EGFR, which led to higher Akt activation. Enhanced NF-?B activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of I?B. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-?B inhibitor, Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-?B inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-?B site. Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-?B activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.

SUBMITTER: Dong YL

PROVIDER: S-EPMC3869803 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NF-κB activation via EGFR-transactivated Akt signaling.

Dong Yuan-Lin YL Kabir Syeda M SM Lee Eun-Sook ES Son Deok-Soo DS

PloS one 20131220 12

Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed ...[more]

PMID: 24376747

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CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NF-?B activation via EGFR-transactivated Akt signaling.

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CXCR2-driven ovarian cancer progression involves upregulation of proinflammatory chemokines by potentiating NF-κB activation via EGFR-transactivated Akt signaling.

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