Cell-Permeable NM23 Blocks the Maintenance and Progression of Established Pulmonary Metastasis

Abstract

Occult metastases are a major cause of cancer mortality, even among patients undergoing curative resection. Therefore, practical strategies to target the growth and persistence of already established metastases would provide an important advance in cancer treatment. Here, we assessed the potential of protein therapy using a cell permeable NM23-H1 metastasis suppressor protein. Hydrophobic transduction domains developed from a screen of 1,500 signaling peptide sequences enhanced the uptake of the NM23 protein by cultured cells and systemic delivery to animal tissues. The cell-permeable (CP)-NM23 inhibited metastasis-associated phenotypes in tumor cell lines, blocked the establishment of lung metastases, and cleared already established pulmonary metastases, significantly prolonging the survival of tumor-bearing animals. Therefore, these results establish the potential use of cell-permeable metastasis suppressors as adjuvant therapy against disseminated cancers. Cancer Res; 71(23); 7216-25. Ó2011 AACR.

A Splicing Variant of NME1 Negatively Regulates NF-κB Signaling and Inhibits Cancer Metastasis by Interacting with IKKβ

“…NME1 also reduces metastasis of colon cancer cells to the liver, potentially by regulating myosin light chain phosphorylation (56). A recent study indicates that a newly developed cell-permeable form of NME1 probably blocks pulmonary metastasis of several cancer cell lines (57). All of the experiments of Lim et al (57), conducted with NME1, reveal that the short form of the protein has moderate but efficient antimetastatic activity, a finding confirmed in our model of metastasis.…”

“…A recent study indicates that a newly developed cell-permeable form of NME1 probably blocks pulmonary metastasis of several cancer cell lines (57). All of the experiments of Lim et al (57), conducted with NME1, reveal that the short form of the protein has moderate but efficient antimetastatic activity, a finding confirmed in our model of metastasis. However, we observed that NME1L dramatically inhibited pulmonary metastasis of cancer cells.…”

Antitumor Activity of Cell-Permeable RUNX3 Protein in Gastric Cancer Cells

“…MTD13, MTD57, and MTD108 were derived from signal sequences from NP_639877, CAD0547.1, NP_629842.1, and NP_003842, respectively, as previously described (26, 27). Histidine-tagged fusion proteins containing EGFP or the full-length 46-kDa RUNX3 protein (33) and MTD13, MTD57, MTD85, MTD108, the FGF4 MTS (M m , AAVLLPVL-LAAP), or a random sequence (S, SANVEPLERL) were cloned into pET-28a(+) (Novagen) and expressed in Escherichia coli BL21-CodonPlus (DE3) cells.…”

“…MITT was used previously to deliver peptides and proteins to a variety of tissues (notably liver, lung, pancreas, and lymphoid tissues), resulting in dramatic protection against lethal inflammatory diseases (21–25), suppression of pulmonary metastases (26), and inhibition of subcutaneous tumor xenografts (27). The technology exploits the ability of hydrophobic macromolecule transduction domains (MTD) to promote bidirectional transfer of peptides and proteins across the plasma membrane (27–29).…”

Progress on Nme (NDP kinase/Nm23/Awd) gene family-related functions derived from animal model systems: studies on development, cardiovascular disease, and cancer metastasis exemplified

“…Other compounds have been reported to elevate tumor cell Nme1 expression as well (Jiang et al 1988;Lin et al 2002;Liu et al 2000;Natarajan et al 2002) and thus are additional candidates at least for preclinical testing. A cell permeable Nme1 construct suppressed development of pulmonary metastases in mice and diminished already established metastases, with a prolongation of overall survival (Lim et al 2011). A peptide that disrupts the interaction of Nme1 and h-Prune has been identified, and preclinical studies were performed in breast and prostate cancers as well as neuroblastoma (Carotenuto et al 2014;Carotenuto et al 2013;D'Angelo et al 2004 Another translational approach is based on the identification of genes which expression patterns were inversely related to that of Nme1 protein.…”