OP449 inhibits breast cancer growth without adverse metabolic effects

Abstract

Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/Akt/mTOR pathway. OP449, a SET inhibitor, decreases Akt/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (p<0.05), and IR phosphorylation was 4.5-fold higher in these mice (p<0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (p<0.05, for both, respectively). Akt and S6RP phosphorylation were 82% and 34% lower in OP449 treated tumors compared with controls (p<0.05, p=0.06, respectively). Akt and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (p<0.01, p<0.05, respectively). However, even with decreased Akt/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449 treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (p<0.01 and p=0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to inhibition of Akt/mTOR signaling, albeit, not leading to metabolic derangements.

Deregulation of SET is Associated with Tumor Progression and Predicts Adverse Outcome in Patients with Early-Stage Colorectal Cancer

“…The upregulation of the SET oncogene has been has been described in several tumor models, and over time it has emerged as a promising molecular target for alternative therapeutic strategies in these cancers [23,24,25,26,27,28,29,30,31,32,33,34,35]. Our previous findings showed that PP2A inhibition is a frequent event in CRC, and we identified SET deregulation as a key mechanism to inhibit PP2A [8].…”

“…In this regard, the use of SET antagonists such as OP449 and FTY720 have emerged in the last years as novel therapeutic approaches in human tumors with SET overexpressed and could also be useful in early-stage CRC patients. OP449 is a specific, cell-penetrating peptide against SET, which has shown anticancer properties in leukemia, prostate, breast and gastric cancers [18,35,42,43], but its potential usefulness in CRC remains to be evaluated. FTY720 is an immunosuppressant currently used in the sclerosis multiple, which has demonstrated potent antitumor effects in many cancers, including CRC [44].…”

“…Furthermore, SET has been found to be de-regulated in some solid tumors and leukemias [23,24,25,26,27,28,29], and it has been proposed as a novel target for anticancer therapy [30,31,32,33,34,35]. Of importance, some data in the literature indicate that SET could also be playing a relevant role in CRC through the regulation of the Wingless-type MMTV integration site family (WNT) signaling pathway [36].…”

Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration

“…Although these compounds generally retain the amphiphilic, sphingolipid-like structure of FTY-720, no assumptions can be made about their off-target effects and safety profiles, and little information is yet available. Apolipoprotein E-derived peptides such as COG1410 also bound to SET, activated PP2A (Christensen et al, 2011) and exerted anti-tumor effects in several experimental models of cancer (Agarwal et al, 2014; Christensen et al, 2011; Fujiwara et al, 2013; Hu et al, 2015; Richard et al, 2016; Shlomai et al, 2017; Switzer et al, 2011). The precise mechanism of action and pathway to translation of these peptides are unclear.…”

Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer

“…The female Rag1 −/− /MKR +/+ mice develop hyperinsulinemia but do not exhibit obesity, hyperglycemia or dyslipidemia [26]. Orthotopic tumor xenografts were performed in Rag1 −/− /MKR +/+ (Rag/MKR) mice and Rag1 −/− (Rag/WT) female mice using MDA-MB-231 cells, as previously described [34]. Tumors derived from the Rag/MKR mice were significantly larger and weighed more than those derived from the MKR tumors, as previously described [34] (Fig.…”