ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells

Abstract

Inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is heavily implicated in the tumorigenesis of prostate cancer. Conversely, the upregulation of the chemokine (CXC) receptor 4 (CXCR4) is associated with prostate cancer progression and metastasis. Studies have shown that loss of PTEN permits CXCR4-mediated functions in prostate cancer cells. Loss of PTEN function is typically due to genetic and epigenetic modulations, as well as active site oxidation by reactive oxygen species (ROS); likewise ROS upregulates CXCR4 expression. Herein, we show that ROS accumulation permitted CXCR4-mediated functions through PTEN catalytic inactivation. ROS increased p-AKT and CXCR4 expression, which were abrogated by a ROS scavenger in prostate cancer cells. ROS mediated PTEN inactivation but did not affect expression, yet enhanced cell migration and invasion in a CXCR4-dependent manner. Collectively, our studies add to the body of knowledge on the regulatory role of PTEN in CXCR4-mediated cancer progression, and hopefully, will contribute to the development of therapies that target the tumor microenvironment, which have great potential for the better management of a metastatic disease.

Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression

“…However, simultaneous SDF1␣/ AM1241 treatment diminished expression of phosphorylated ERK1/2. We previously demonstrated in prostate cancer cells that treatment with SDF1␣ resulted in phosphorylation of ERK1/2 in a biphasic manner, whereas no changes in AKT phosphorylation status were observed (77,78). Likewise, we observed that combined agonist treatment with SDF1␣/ AM1241 did not significantly reduce the phosphorylation status of AKT compared with cells treated with SDF1␣ alone in MDA-MB-231 cells (Fig.…”

“…In the context of this study, the induced dimer diminished subsequent expression of phosphorylated ERK1/2 that would have otherwise come from individually activated CXCR4. In our experience working with SDF1␣ (77,78) and as reported by Nasser et al (71), ERK1/2 is more responsive to the SDF1␣/CXCR4 signaling axis than AKT, especially in the context of cell migration. Robust CB2-mediated activation of ERK1/2 is cell line-specific, agonist-specific, and/or coupled with other signaling pathways (89,90).…”

“…AM1241 Modulated SDF1␣-induced Phosphorylation of ERK1/2-A common and pharmacologically essential attribute of GPCR heterodimers is the ability to amplify or antagonize downstream signaling that would otherwise result from activation of single constituent receptors (50,58,68,71,78). Therefore, we investigated whether changes occurred in the expression levels of phosphorylated kinases ERK1/2 and AKT when cancer cells were simultaneously stimulated with SDF1␣ and AM1241.…”

“…3A). Because, aggressive cancer cells can produce and secrete endogenous SDF1␣, we antagonized endogenous SDF1␣ binding to CXCR4 with the chemical inhibitor AMD3100 (77,78), which diminished red fluorescence in AM1241-treated cells (Fig. 4, C and D).…”

Prostate Cancer Dephosphorylation Atlas

“…Through combined pharmacological inhibition of both pathways, the authors could achieve near-complete prostate cancer regressions in a PTEN-deficient murine model and in human xenografts (Carver et al, 2011). Recent studies have also implicated PTEN loss in chemokine receptor 4 (CXCR4)-mediated prostate cancer progression and metastasis, as well as showing that reactive oxygen species (ROS) can increase this outcome through direct inactivation of PTEN by active site oxidation (Chetram et al, 2011).…”