Disruption of cell-matrix interactions can lead to anoikis-apoptosis due to loss of matrix contacts. We previously showed that Nerve/glial antigen 2 (NG2) is a novel anoikis receptor. Specifically, overexpression of NG2 leads to anoikis propagation, whereas its suppression leads to anoikis attenuation. Interestingly, NG2 expression decreases in late anoikis, suggesting that NG2 reduction is also critical to this process. Thus, we hypothesized that NG2 undergoes cleavage to curtail anoikis propagation. Further, since matrix metalloproteinases (MMPs) cleave cell surface receptors, play a major role in modulating apoptosis, and are associated with death receptor cleavage during apoptosis, we further hypothesized that cleavage of NG2 could be mediated by MMPs to regulate anoikis. Indeed, anoikis conditions triggered release of the NG2 extracellular domain into condition media during late apoptosis, and this coincided with increased MMP-13 expression. Treatment with an MMP-13 inhibitor and MMP-13 siRNA increased anoikis, since these treatments blocked NG2 release. Further, NG2-positive cells exhibited increased anoikis upon MMP-13 inhibition, whereas MMP-13 inhibition did not increase anoikis in NG2-null cells, corroborating that retention of NG2 on the cell membrane is critical for sustaining anoikis, and its cleavage for mediating anoikis attenuation. Similarly, NG2 suppression with siRNA inhibited NG2 release and anoikis. In contrast, MMP-13 overexpression or exogenous MMP-13 reduced anoikis by more effectively shedding NG2. In conclusion, maintenance of NG2 on the cell surface promotes anoikis propagation, whereas its shedding by MMP-13 actions attenuates anoikis. Given that these findings are derived in the context of periodontal ligament fibroblasts, these data have implications for periodontal inflammation and periodontal disease pathogenesis.

Prostate and breast cancer are the current leading causes of new cancer cases in males and females, respectively. Phosphatidylserine (PS) is an essential lipid that mediates macrophage efferocytosis and is dysregulated in tumors. Therefore, developing therapies that selectively restore PS may be a potential therapeutic approach for carcinogenesis. Among the nanomedicine strategies for delivering PS, biocompatible gold nanoparticles (AuNPs) have an extensive track record in biomedical applications. In this study, we synthesized biomimetic phosphatidylserine-caped gold nanoparticles (PS-AuNPs) and tested their anticancer potential in breast and prostate cancer cells in vitro. We found that both cell lines exhibited changes in cell morphology indicative of apoptosis. After evaluating for histone-associated DNA fragments, a hallmark of apoptosis, we found significant increases in DNA fragmentation upon PS-AuNP treatment compared to the control treatment. These findings demonstrate the use of phosphatidylserine coupled with gold nanoparticles as a potential treatment for prostate and breast cancer. To the best of our knowledge, this is the first time that a phosphatidylserine-capped AuNP has been examined for its therapeutic potential in cancer therapy.