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Abstract
Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent.
Highlights
The Nm23 gene encodes nucleoside diphosphate kinase (NDPK), which catalyzes the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleoside triphosphates[1]
We demonstrated that NDPK activity is crucial for tumor metastasis suppression of Nm23-H1 and that this activity is regulated by oxido-reduction system
In our efforts to meet this need, we looked for chemical approaches to enhancing the cellular activity of Nm23-H1 based on redox regulation of NDPK activity[20]
Summary
The Nm23 gene encodes nucleoside diphosphate kinase (NDPK), which catalyzes the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleoside triphosphates[1]. Nm23-H1 is known to possess multiple enzymatic activities including NDPK, protein histidine kinase, and 3′–5′ exonuclease[14,15]. Among these multiple enzyme activities, NDPK activity is crucial for Nm23-H1 mediated biological functions including cytoskeleton organization, insulin secretion, and endocytosis[11,13,16]. The Nm23-H1 mutant C109A is not inhibited by oxidative stress, but shows constitutively active NDPK activity and suppresses invasion and migration in MDA-MB-231 breast cancer cells[20]. These studies confirmed that activation of NDPK leads to the inhibition or prevention of tumor metastasis. These unsuccessful attempts to increase cellular level of Nm23-H1 indicate that new approaches are needed to confirm the potential of increasing the cellular level of Nm23-H1 in preventing or arresting tumor metastasis
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