The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Abstract

Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for non-metastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.

Keywords: Apoptosis; Cell migration; Cftr; Dynamin; Metastasis inhibitor; NDPK; NM23; Phagocytosis; Phosphohistidine.

Fig. 1

The role of NM23-H1, NM23-M1, AWD and NDK-1 in processes related to the metastatic cascade. Metastasis formation is a complex and multistep process, as a tumor cell acquires invasive characteristics and passes through the steps of the metastatic cascade. In case of carcinomas, tumor cells of epithelial origin detach from the primary tumor, gaining access to the surrounding stroma by breaching the basement membrane (invasion), then they enter the microvasculature of the lymphatic or blood system (intravasation). Next they survive in the circulation avoiding immune surveillance and translocate to distant tissues. Following extravasation tumor cells (micrometastases) have to survive in a new microenvironment of the distant tissue. After cancer cells have spread from the primary tumor to a secondary site, just a small number of them can conform to this new environment and form micro- and macrometastases. The majority of these tumor cells step into a dormant state or forced into apoptotic cell death by the signals from the new microenvironment. Successful metastatic colonization with formation of macrometastases often depends on avoidance of apoptotic signals and employing proliferation signals by the micrometastases. Subsequently secondary colonies will be eventually able to establish new blood supplies. If any of these steps fail to occur, metastases cannot develop. In this review we emphasize three major processes in which NM23-H1 and its homologs, AWD (D. melanogaster), NDK-1 (C. elegans) and NM23-M1 (M. musculus) have an important role. These processes are linked to different steps of the metastatic cascade. NM23-H1, AWD, and NDK-1 inhibit cell migration (NM23-H1 suppresses invasion as well). NM23-H1 was shown to inhibit proliferation. NM23-H1, NM23-M1 and NDK-1 promote phagocytosis, whereby apoptotic cell debris are eliminated by macrophages. Cell migration plays a role in an early step of the metastatic cascade, whereas proliferation and apoptosis are processes influencing a late step, metastatic colonization.