Targeting inhibitor 2 of protein phosphatase 2A as a therapeutic strategy for prostate cancer treatment

Abstract

Inhibitor 2 of protein phosphatase 2A (I2PP2A), a biological inhibitor of the cellular serine/threonine protein phosphatase PP2A, is associated with numerous cellular processes that often lead to the formation and progression of cancer. In this study we hypothesized that targeting the inhibition of I2PP2A's multiple functions in prostate cancer cells might prevent cancer progression. We have investigated the effect of the small chain C6-ceramide, known to be a bioactive tumor suppressor lipid, on I2PP2A function, thereby affecting c-Myc signaling and histone acetylation in cells. Our data indicated that C6-ceramide treatment of prostate cancer cells induces cell death in PC-3, DU145, and LNCaP cells, but not normal prostate epithelial cells. C6-ceramide was able to disrupt the association between PP2A and I2PP2A. C6-ceramide inhibits I2PP2A's upregulation of c-Myc and downregulation of histone acetylation in prostate cancer cells. Our data indicated that targeting cancer related signaling pathways through I2PP2A using ceramide as an anti-I2PP2A agent could have beneficial effects as a therapeutic approach to prevent prostate cancer.

Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression

“…This is consistent with a report that SK2 regulates Myc mRNA and protein by altering HDAC activity [19]. Alternatively, effects of ABC294640 may be mediated by ceramide accumulation following SK2 inhibition since ceramide is reported to activate protein phosphatase 2A (PP2A), resulting in decreased Myc expression, which is reversible by PP2A inhibitors [35]. To determine if ABC294640 decreases Myc through the ceramide-PP2A pathway, LNCaP cells were treated with vehicle, ABC294640 alone, or ABC294640 in combination with PP2A inhibitor, okadaic acid.…”

“…In other models, ABC294640 promotes cell apoptosis and downregulates Myc protein in a pS6-mediated fashion that is rescued by MG132 and implicates a role for the proteasome [18]. Finally, ceramide has been reported to decrease Myc protein expression in PCa cells by a protein phosphatase 2A-dependent mechanism [35]. However, our data argue this mechanism is not active in PCa cells since inhibition of PP2A did not attenuate ABC294640-induced down-regulation of Myc or AR.…”

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

“…The SET oncogene has been reported to be upregulated in several types of cancer and it has been proposed as a candidate to develop novel molecular targeted therapies (21)(22)(23). Our previous results showed that PP2A inactivation is a common event in colorectal cancer and we identified SET deregulation as a possible contributing mechanism to inhibit PP2A in a set of 21 samples of patients with primary colorectal cancer (32).…”

“…For instance, it has been reported that SET activates the transcription factor AP-1, deregulates AKT signaling, inhibits the DNase activity of the tumor-suppressor NM23-H1, or negatively regulates p53 acetylation, thus repressing its activity (12)(13)(14)(15)(16). Moreover, SET is overexpressed in several neoplasms (17)(18)(19)(20)(21) and it has been proposed as a novel molecular target for anticancer therapy (20)(21)(22)(23). The transcription factor EVI-1 and the miR199b have been described to regulate SET expression in acute myeloid leukemia and choriocarcinoma (18,24).…”

The NMR‐based characterization of the FTY720‐SET complex reveals an alternative mechanism for the attenuation of the inhibitory SET‐PP2A interaction

“…In "compact" confirmation, the sphingosine backbone and fatty acyl chain would run parallel to each other. We used D-e-C6P, a highly soluble ceramide analog (32,57), to determine whether SET binding requires its "extended" or "compact" conformation. Initial NMR studies illustrated that the C6P could serve as a molecular probe by monitoring chemical shift changes (Supplemental Fig.…”