Date Published: September 19, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Junko Okabe-Kado, Takashi Kasukabe, Yasuhiko Kaneko.
An elevated serum level of NM23-H1 protein is a poor prognostic factor in patients with various hematologic malignancies. The extracellular NM23-H1 protein promotes the in vitro growth and survival of acute myelogenous leukemia (AML) cells and inversely inhibits the in vitro survival of normal peripheral blood monocytes in primary culture at concentrations equivalent to the levels found in the serum of AML patients. The growth and survival promoting activity to AML cells is associated with cytokine production and activation of mitogen-activated protein kinases (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways. Inhibitors specific for MAPK signaling pathways inhibit the growth/survival-promoting activity of NM23-H1. These findings indicate a novel biological action of extracellular NM23-H1 and its association with poor prognosis. These results suggest an important role of extracellular NM23-H1 in the malignant progression of leukemia and a potential therapeutic target for these malignancies.
The NM23 gene was identified by differential hybridization of a cDNA library with total RNA extracted from slightly and highly metastatic melanoma cell lines . The NM23 gene has been identified as a family of genes encoding different isoforms of nucleoside diphosphate kinase (NDPK) . NM23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis, and the mechanisms of these pleiotropic effects are not well understood [3, 4]. Ten isotypes of the human NM23 gene have been identified . Among these, only NM23-H1 and NM23-H2 have been studied extensively in human cancers. The level of NM23-H1 expression is inversely correlated with the tumor’s metastatic potential in experimental rodent cells and in human tumors, such as breast, ovarian, cervical, and gastric cancer, hepatocellular carcinoma, and melanomas . Exogenous overexpression of NM23-H1 reduces the metastatic potential of multiple types of cancer cells and suppresses in vitro tumor cell motility and invasion ; therefore, NM23-H1 is implicated in the regulation of metastasis in a variety of human cancers, and its overexpression predicts a favorable patient prognosis. In contrast, elevated NM23-H1 expression is related to a more aggressive disease in neuroblastoma and many hematologic malignancies [7–11]. The significance of NM23-H1 overexpression as a prognostic factor is dependent on tumor cell types although the mechanism of this discrepancy is unknown.
NM23 has no secretion signal peptide but is nonetheless detected in conditioned medium of some tumor cell lines and in body fluids [14, 25–28]. The mechanisms by which NM23-H1 protein is secreted into the extracellular environment are unclear. Recently, Keller et al.  showed a new pathway for the secretion of many inflammatory response proteins without signal sequences. This unconventional secretion required the catalytic activity of caspase-1 and could rapidly release a wide variety of proteins involved in trigger detoxification, tissue repair, and cell survival. Furthermore, an exosome-associated export pathway of a number of proteins without signal sequences from the cells is reported . It would be interesting to examine whether these new secretion pathways secrete NM23 protein; however, unlike secretion, it might be the release of NM23 protein by dying tumor cells overexpressing NM23.
The mechanisms by which NM23-H1 protein is secreted into the extracellular environment and affects the outcome of patients are unclear. Very little information is available concerning extracellular expression and function although many studies have examined the expression of intracellular NM23 proteins; therefore, we focused on extracellular NM23-H1 protein derived from tumor cells, because its clinical significance is higher than that of intracellular overexpression , and the elevated extracellular expression of NM23-H1 has not been found in normal healthy plasma . To demonstrate the clinical importance of extracellular NM23-H1 protein as a therapeutic target of patients with hematologic malignancies, we surveyed the biological functions of extracellular NM23-H1 protein. First, we investigated the extracellular functions of recombinant NM23 (rNH23) proteins on the survival and growth of normal and leukemic PBMNC and their association with the poor prognosis of AML patients.
Recent advances in genome technologies and the ensuing outpouring genomic information-related cancer have accelerated the conversion from a genome discovery into a tangible clinical endpoint. Successful examples of translating cancer genomics into therapeutics and diagnostics show the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential . NM23-H1 plays complex roles in the development of diverse cancers including carcinoma, high-grade lymphomas, and AML. As has been mentioned, in the case of AML and lymphomas, serum NM23-H1 protein is elevated with highest levels correlating with poorest prognosis. Moreover, the data of Lilly and colleagues  and our recent studies [33, 34] strongly indicate that extracellular NM23-H1 can act as a tumor-derived growth/survival factor in AML (Figure 3). These findings suggest an important biological role of extracellular NM23-H1 in the malignant progression/poor prognosis of leukemia and a potential therapeutic target for these malignancies.