MMP-2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma.

BACKGROUND: Doxorubicin, a first-line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase and zinc-dependent endopeptidase, is well-known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP-2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP-2 activity is regulated by the non-receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C-terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK). AIM: In this study, we reveal that the MMP-2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells. METHODS AND RESULTS: We show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP-2 gene or overexpressing CHK/MATK. Our findings highlight the MMP-2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its role in suppressing on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma. CONCLUSION: By targeting the MMP-2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.

RYBP Sensitizes Cancer Cells to PARP Inhibitors by Regulating ATM Activity.

Ring1 and YY1 Binding Protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. Previously, we showed that RYBP, along with other PRC1 members, is also involved in the DNA damage response. RYBP inhibits recruitment of breast cancer gene 1(BRCA1) complex to DNA damage sites through its binding to K63-linked ubiquitin chains. In addition, ataxia telangiectasia mutated (ATM) kinase serves as an important sensor kinase in early stages of DNA damage response. Here, we report that overexpression of RYBP results in inhibition in both ATM activity and recruitment to DNA damage sites. Cells expressing RYBP show less phosphorylation of the ATM substrate, Chk2, after DNA damage. Due to its ability to inhibit ATM activity, we find that RYBP sensitizes cancer cells to poly-ADP-ribose polymerase (PARP) inhibitors. Although we find a synergistic effect between PARP inhibitor and ATM inhibitor in cancer cells, this synergy is lost in cells expressing RYBP. We also show that overexpression of RYBP hinders cancer cell migration through, at least in part, ATM inhibition. We provide new mechanism(s) by which RYBP expression may sensitize cancer cells to DNA damaging agents and inhibits cancer metastasis.

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu.

Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.