MT1-MMP as a Key Regulator of Metastasis

Abstract

Membrane type1-matrix metalloproteinase (MT1-MMP) is a member of metalloproteinases that is tethered to the transmembrane. Its major function in cancer progression is to directly degrade the extracellular matrix components, which are mainly type I–III collagen or indirectly type IV collagen through the activation of MMP-2 with a cooperative function of the tissue inhibitor of metalloproteinase-2 (TIMP-2). MT1-MMP is expressed as an inactive form (zymogen) within the endoplasmic reticulum (ER) and receives truncation processing via furin for its activation. Upon the appropriate trafficking of MT1-MMP from the ER, the Golgi apparatus to the cell surface membrane, MT1-MMP exhibits proteolytic activities to the surrounding molecules such as extracellular matrix components and cell surface molecules. MT1-MMP also retains a non-proteolytic ability to activate hypoxia-inducible factor 1 alpha (HIF-1A) via factors inhibiting the HIF-1 (FIH-1)-Mint3-HIF-1 axis, resulting in the upregulation of glucose metabolism and oxygen-independent ATP production. Through various functions of MT1-MMP, cancer cells gain motility on migration/invasion, thus causing metastasis. Despite the long-time efforts spent on the development of MT1-MMP interventions, none have been accomplished yet due to the side effects caused by off-target effects. Recently, MT1-MMP-specific small molecule inhibitors or an antibody have been reported and these inhibitors could potentially be novel agents for cancer treatment.

Membrane trafficking alterations in breast cancer progression

“…ARF6 activity and its effectors JIP3 and JIP4 have been associated with MDA-MB-231 cell invasion through invadopodia-mediated mechanisms ( Marchesin et al, 2015 ). In particular, the authors found that the binding of active ARF6 to JIP3/JIP4 regulates the trafficking and exocytosis of MT1-MMP, a key regulator of invadopodia function ( Tanaka and Sakamoto, 2023 ). Furthermore, this study showed that the regulation of MT1-MMP trafficking occurs via the recruitment of motor proteins (dynactin-dynein and kinesin-1) by JIP3/JIP4 ( Marchesin et al, 2015 ).…”

Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis

“…The molecular mechanism underlying the initiation and sustenance the metastasis of tumor is intricate ( Tanaka and Sakamoto, 2023 ). The mechanism encompasses the establishment of a tumor microenvironment, the process of vascular remodeling, the acquisition of tumor cell invasiveness, and the reduction in tumor cell consumption ( Figure 3 ).…”

Analysis of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP, MMP14) in Eutopic and Ectopic Endometrium and in Serum and Endocervical Mucus of Endometriosis

“…The importance of MT1-MMP in tumor metastasis has increased significantly in recent years [57]. Not only the degradation of collagen type 1-3 is important, but also the involvement of the enzyme in the migration and invasion of tumor cells has raised hopes for a successful therapy with specific inhibitors [57].…”

“…The importance of MT1-MMP in tumor metastasis has increased significantly in recent years [57]. Not only the degradation of collagen type 1-3 is important, but also the involvement of the enzyme in the migration and invasion of tumor cells has raised hopes for a successful therapy with specific inhibitors [57]. Thus, our observation of an increased abundance of MT1-MMP, especially in adenomyosis, might be interesting for the development of future therapies against the disease.…”