Overexpression of xCT induces up-regulation of 14-3-3β in Kaposi's sarcoma

Abstract

KSHV (Kaposi's sarcoma-associated herpesvirus), or HHV-8 (human herpesvirus 8), is associated with the pathogenesis of KS, the most common AIDS-related malignancy. xCT (functional subunit of the cystine/glutamate transporter xc− system) is known as the HHV-8 fusion-entry receptor as well as an oncogenic protein. How the xCT triggers the signal transduction of HHV-8 infection and the cell proliferation remains incomplete. We found that xCT was overexpressed in KS tissues and HHV-8-positive BCBL-1 cells. When xCT cDNA plasmids were transfected into the HHV-8-negative BJAB cells, the expression of 14-3-3β and cell growth rate were increased. In contrast, the expression of 14-3-3β and the cell growth rate of HHV-8-positive BCBL-1 cells were suppressed by either xCT siRNA (short interfering RNA) or an xCT inhibitor, sulfsalazine. These results suggest that 14-3-3β is a downstream effector of xCT in KS to mediate the cell proliferation.

Kaposi's Sarcoma-Associated Herpesvirus Suppression of DUSP1 Facilitates Cellular Pathogenesis following De Novo Infection

“…Our data are consistent with published data indicating that the upregulation of xCT by miR-K12-11 results in xCT-mediated activation of 14-3-3␤ expression, which, in turn, leads to 14-3-3␤-mediated transcriptional repression of DUSP1 (32,33,51,53,54). For additional confirmation, we show that targeting 14-3-3␤ restores DUSP1 expression and reduces the production of promigratory factors and endothelial cell invasiveness under conditions of either KSHV infection or ectopic miR-K12-11 expression.…”

“…Existing data suggest that the 14-3-3␤/14-3-3␤ interactant 1 (FBI1) complex binds the promoter region of DUSP1 and acts as a transcriptional repressor, thereby increasing ERK activation and promoting anchorage-independent growth, tumorigenicity, and metastasis (51). One study also reported that overexpression of the amino acid transporter xCT (a fusion/entry receptor for KSHV [52]) induces upregulation of 14-3-3␤ expression in KSHV-infected cells through mechanisms not yet defined (53). We have reported previously that KSHV-encoded miR-K12-11 upregulates xCT expression through repression of BACH-1, a negative transcriptional regulator of xCT (32), and others have confirmed that miR-K12-11 targets the BACH-1 3= UTR (33,54).…”

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen and Angiogenin Interact with Common Host Proteins, Including Annexin A2, Which Is Essential for Survival of Latently Infected Cells

“…Latent protein LANA-2, detected exclusively in KSHV-infected B cells, has been shown to interact with 14-3-3 proteins and inhibit FOXO3␣ transcription factor (80). In another study, overexpression of xCT, an HHV-8 fusion-entry receptor, was shown to induce upregulation of 14-3-3␤ in KS (118). LANA-1 could interact with 14-3-3 in endothelial cells to function either in ways similar to those of LANA-2 or via a different mechanism to prevent cell cycle arrest.…”

14-3-3β regulates the proliferation of glioma cells through the GSK3β/β-catenin signaling pathway

“…Upregulation of 14-3-3β promoted cell proliferation and tumor formation by the mitogen-activated protein kinase (MAPK)-dependent signaling pathway in NIH3T3 cells (39). Increased expression of 14-3-3β was observed in Kaposi's sarcoma and papillary thyroid carcinomas and promoted cell proliferation and tumor progression (41,42). Our previous studies demonstrated that 14-3-3β expression increased with the degree of human astrocytoma.…”

“…14-3-3β is expressed in tumor tissues and cell lines of many types of cancers including lung, prostate and breast cancer (42,43). However, the mechanism of 14-3-3β in the regulation of cancer cells is quite complicated.…”