Abstract
BackgroundFenretinide (4-HPR) is a synthetic retinoid that exhibits potent antitumor and chemopreventive activities against different malignancies, including ovarian tumors. We previously showed that in ovarian cancer cells, 4-HPR induces apoptosis through a signaling cascade starting from reactive oxygen species (ROS) generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and induction of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Since recent studies have shown that the oncogene ALL1-fused from chromosome 1q (AF1q), a retinoic acid target gene, is implicated in apoptosis induction by several therapeutic agents, we investigated its possible involvement in the apoptosis induced by 4-HPR in ovarian cancer cells.Methodology/Principal FindingsProtein expression analysis, performed in ovarian cancer cells and extended to other histotypes (breast, neuroblastoma, and cervical), revealed that 4-HPR enhanced AF1q expression in cancer cells sensitive to the retinoid but not in resistant cells. Through gene silencing, AF1q was found functionally involved in 4-HPR-induced apoptosis in A2780, an ovarian cancer cell line highly sensitive to retinoid growth inhibitory and apoptotic effects. Inhibition of the signaling intermediates of the 4-HPR apoptotic cascade showed that AF1q upregulation was depended on prior generation of ROS, induction of ER stress response, JNK activation, and PLAB upmodulation. Finally, we found that direct overexpression of AF1q, in the absence of external stimuli, increased apoptosis in ovarian cancer cell lines.Conclusions/SignificanceThe study expands the knowledge of the 4-HPR mechanism of action, which has not yet been completely elucidated, identifying AF1q as a novel mediator of retinoid anticancer activity. In addition, we demonstrate, for the first time, that AF1q plays a role in the onset of basal apoptosis in ovarian cancer cells, thus providing new information about the activity of this protein whose biologic functions are mostly unknown.
Highlights
IntroductionA large family of natural and synthetic compounds structurally related to vitamin A (retinol), are essential signaling molecules that regulate a wide variety of biological processes such as embryonic development, differentiation, maintenance of epithelial tissue, reproduction, vision, proliferation and apoptosis [1,2]
Retinoids, a large family of natural and synthetic compounds structurally related to vitamin A, are essential signaling molecules that regulate a wide variety of biological processes such as embryonic development, differentiation, maintenance of epithelial tissue, reproduction, vision, proliferation and apoptosis [1,2]
To assess whether 4-HPR-induced ALL1-fused from chromosome 1q (AF1q) upregulation was restricted to A2780 cells or represented a distinctive mode of action of the retinoid, we extended the analysis of AF1q expression to others human cancer cells with different sensitivities to the antiproliferative effect of 4-HPR
Summary
A large family of natural and synthetic compounds structurally related to vitamin A (retinol), are essential signaling molecules that regulate a wide variety of biological processes such as embryonic development, differentiation, maintenance of epithelial tissue, reproduction, vision, proliferation and apoptosis [1,2]. 4-HPR has been shown to inhibit cell proliferation and to promote apoptosis mediated, at least in part, by the generation of reactive oxygen species (ROS) and consequent oxidative stress [8,9,10,11]. We previously provided evidence that, in ovarian cancer cells, 4-HPR induced apoptosis through a signaling cascade starting from ROS production and involving endoplasmic reticulum (ER) stress response, Jun Nterminal Kinase (JNK) activation, and induction of the proapoptotic PLAcental Bone morphogenetic protein (PLAB, known as NAG-1, GDF15, MIC-1, PDF, and PTGFB) (ROS R ER stress R JNK R PLAB) [11,12]. We previously showed that in ovarian cancer cells, 4-HPR induces apoptosis through a signaling cascade starting from reactive oxygen species (ROS) generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and induction of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Since recent studies have shown that the oncogene ALL1-fused from chromosome 1q (AF1q), a retinoic acid target gene, is implicated in apoptosis induction by several therapeutic agents, we investigated its possible involvement in the apoptosis induced by 4-HPR in ovarian cancer cells
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