The tissue inhibitor of metalloproteinases-1 (TIMP-1) promotes survival and migration of acute myeloid leukemia cells through CD63/PI3K/Akt/p21 signaling

Abstract

We and others have shown that the Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), a member of the inflammatory network exerting pleiotropic effects in the bone marrow (BM) microenvironment, regulates the survival and proliferation of different cell types, including normal hematopoietic progenitor cells. Moreover, TIMP-1 has been shown to be involved in cancer progression. However, its role in leukemic microenvironment has not been addressed. Here, we investigated the activity of TIMP-1 on Acute Myelogenous Leukemia (AML) cell functions. First, we found that TIMP-1 levels were increased in the BM plasma of AML patients at diagnosis. In vitro, recombinant human (rh)TIMP-1 promoted the survival and cell cycle S-phase entry of AML cells. These kinetic effects were related to the downregulation of cyclin-dependent kinase inhibitor p21. rhTIMP-1 increases CXCL12-driven migration of leukemic cells through PI3K signaling. Interestingly, activation of CD63 receptor was required for TIMP-1's cytokine/chemokine activity. Of note, rhTIMP-1 stimulation modulated mRNA expression of Hypoxia Inducible Factor (HIF)-1α, downstream of PI3K/Akt activation. We then co-cultured AML cells with normal or leukemic mesenchymal stromal cells (MSCs) to investigate the interaction of TIMP-1 with cellular component(s) of BM microenvironment. Our results showed that the proliferation and migration of leukemic cells were greatly enhanced by rhTIMP-1 in presence of AML-MSCs as compared to normal MSCs. Thus, we demonstrated that TIMP-1 modulates leukemic blasts survival, migration and function via CD63/PI3K/Akt/p21 signaling. As a “bad actor” in a “bad soil”, we propose TIMP-1 as a potential novel therapeutic target in leukemic BM microenvironment.

TIMP-1 promotes hypermigration of Toxoplasma-infected primary dendritic cells via CD63–ITGB1–FAK signaling

“…In normal and cancer cells, activated ITGB1 recruits focal adhesion kinase (FAK), which auto-phosphorylates Tyr-397 and subsequently recruits SRC kinase (Ando et al, 2018) and phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) (Toricelli et al, 2013), leading to MAPK activation and cytoskeletal rearrangements (Jung et al, 2006;Ando et al, 2018). Mounting evidence suggests TIMP-1-CD63 signaling functions as a key regulator of cancer cell survival (Jung et al, 2006), metastasis (Forte et al, 2017) and stem cell migration (Wilk et al, 2013;Lee et al, 2014). However, the role of TIMP-1-CD63 signaling in leukocyte biology remains enigmatic.…”

MiR-375 attenuates injury of cerebral ischemia/reperfusion via targetting Ctgf

“…It has been known that the PI3K/AKT signaling and p21 are closely related to cell survival, growth, and migration [ 15 , 16 ]. Thus, we next determined whether this protective role of miR-375 against H/R injury was associated with PI3K/AKT and p21-dependent signaling pathway.…”

T Cell Co-Stimulation: Inhibition of Immunosuppression?

“…As far as I have been able to determine, there are no reports that CD28 ligation influences TIMP expression. However, a possible relationship between LRP1, TIMP-1, and CD28 is suggested by the fact that CD28 co-stimulation enhances PI3K activity ( 46 ), TIMP-1 signals through PI3K ( 47 ), and LRP1 is a major activator of PI3K ( 36 , 37 ). It is also worthy to note that T cell expression of TIMP-1 is increased in experimental inflammatory disease ( 48 ), which supports the possibility that CD28 co-stimulation contributes to this increase.…”