Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer

Abstract

Advanced breast cancer requires systemic treatment, therefore developing an efficient and safe strategy is urgently needed. To ensure the success of target therapy, we have developed a breast cancer-specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier) to target PEA-15 (Phosphoprotein enriched in astrocytes) in advanced breast tumors. PEA-15 contains a death effector domain that sequesters extracellular signal-regulated kinase (ERK) in cytoplasm, thereby inhibiting cell proliferation and inducing apoptosis. T-VISA-PEA-15 was found to be highly specific, selectively express PEA-15 in breast cancer cells, and induce cancer-cell killing in vitro and in vivo without affecting normal cells. Moreover, intravenously treatment with T-VISA-PEA-15 coupled with liposome nanoparticles attenuated tumor growth and prolonged survival in mice bearing advanced breast tumors. Importantly, there was virtually no severe toxicity when PEA-15 is expressed by our T-VISA system compared with cytomegalovirus (CMV) promoter. Thus, our findings demonstrate an effective cancer-targeted therapy that is worthy of development in clinical trials eradicating advanced breast cancer.

Non-Phosphorylatable PEA-15 Sensitises SKOV-3 Ovarian Cancer Cells to Cisplatin

“…A total of 444 genes were exclusively differentially regulated in cisplatin-treated SKOV-3-AA cells with UGT1A family representing the most significantly affected pathway (glucuronidation). UGTs catalyse the addition of a β-glucuronic acid moiety to a variety of nucleophilic sites of xenobiotics and endogenous compounds including bilirubin, steroids, bile acids, drugs and other carcinogenic and toxic compounds [58], and have been linked to drug resistance in cancer. The downregulation of UGT1A enzymes upon cisplatin exposure is likely to be a consequence of suppression of upstream signalling via Nrf2 pathway, which was also affected in response to cisplatin treatment.…”

“…To target PEA-15 in advanced breast tumours, Xie et al developed a breast cancer specific construct (T-VISA) composed of the human telomerase reverse transcriptase (hTERT; T) promoter and a versatile transgene amplification vector VISA (VP16-GAL4-WPRE integrated systemic amplifier). T-VISA-PEA-15 was found to be highly specific, to selectively express PEA-15 in breast cancer cells, and to induce cancer cell killing in vitro and in vivo without affecting normal cells [58]. a similar construct with PEA-15AA would be of interest for ovarian cancer in order to investigate if the efficacy of cisplatin treatment can be improved.…”

The protein phosphatase 4 - PEA15 axis regulates the survival of breast cancer cells

“…The enzyme is involved in the regulation of microtubule growth and organization at the centrosomes [9], centrosome maturation in mitosis and meiosis and DNA damage response [8,44]. Recent evidence suggested that PP4c controls neural progenitor cell proliferation and differentiation in the mouse neocortex by regulating the phosphorylation status of Nuclear distribution protein nudE-like1 (Ndel1) [34]. PP4c interacts with and down-regulates insulin receptor substrate 4 (IRS4) following tumour necrosis factor-alpha (TNF-α) stimulation leading to the inhibition of the anti-apoptotic function of IRS4 [45].…”

“…It is implicated in the dysregulation of many signalling pathways involved in cancer progression and tumorigenesis and it has been described to act as both a tumour suppressor and a tumour promoter, dependent on its phosphorylation status [30][31][32]. The PEA15 gene is amplified in breast cancer, as well as in other cancers [33], and the unphosphorylated form of PEA15 is more potent than the phosphorylated form in suppressing tumorigenicity in breast cancer [34]. While several kinases have been reported to be involved in the phosphorylation of PEA15 including Akt, Ca2+/calmodulin-dependent protein kinase (CaMKII) and AMP-activated protein kinase (AMPK) [35,36], the dephosphorylation of PEA15 is much less understood.…”

Engineering and cytosolic delivery of a native regulatory protein and its variants for modulation of ERK2 signaling pathway

“…Whereas phosphorylated PEA‐15 has a negligible inhibitory effect on the function of ERK2, non‐phosphorylated PEA‐15 is known to directly bind to ERK2 and block its functions, such as substrate binding and nuclear translocation (Callaway, Abramczyk, Martin, & Dalby, ; Krueger, Chou, Glading, Schaefer, & Ginsberg, ; Trencia et al, ). With such a function, PEA‐15 itself has gained significant attention as a potential therapeutic for cancer treatment (Lee et al, ; Xie et al, ; Xie et al, ). The development of PEA‐15 as a therapeutic agent has several barriers, however, such as a low binding affinity (∼3.4 μM) for ERK2 and the lack of an efficient intracellular delivery system (Mace et al, ).…”