Morus alba Leaf Lectin (MLL) Sensitizes MCF-7 Cells to Anoikis by Inhibiting Fibronectin Mediated Integrin-FAK Signaling through Ras and Activation of P38 MAPK

Abstract

Lectins are a unique class of carbohydrate binding proteins/glycoproteins, and many of them possess anticancer properties. They can induce cell cycle arrest and apoptosis, inhibit protein synthesis, telomerase activity and angiogenesis in cancer cells. In the present study, we have demonstrated the effect of Morus alba leaf lectin (MLL) on anoikis induction in MCF-7 cells. Anoikis induction in cancer cells has a significant role in preventing early stage metastasis. MLL treatment in monolayers of MCF-7 cells caused significant detachment of cells in a time and concentration dependent manner. The detached cells failed to re-adhere and grew even to culture plates coated with different matrix proteins. DNA fragmentation, membrane integrity studies, annexin V staining, caspase 9 activation and upregulation of Bax/Bad confirmed that the detached cells underwent apoptosis. Upregulation of matrix metalloproteinase 9 (MMP-9) caused a decrease in fibronectin (FN) production which facilitated the cells to detach by blocking the FN mediated downstream signaling. On treatment with MLL, we have observed downregulation of integrin expression, decreased phosphorylation of focal adhesion kinase (FAK), loss in FAK-integrin interaction and active Ras. MLL treatment downregulated the levels of phosphorylated Akt and PI3K. Also, we have studied the effect of MLL on two stress activated protein kinases p38 MAPK and JNK. p38 MAPK activation was found to be elevated, but there was no change in the level of JNK. Thus our study substantiated the possible antimetastatic effect of MLL by inducing anoikis in MCF-7 cells by activation of caspase 9 and proapoptotic Bax/Bad by blockage of FN mediated integrin/FAK signaling and partly by activation of p38 MAPK.

Silencing MR-1 attenuates atherosclerosis in ApoE−/− mice induced by angiotensin II through FAK-Akt–mTOR-NF-kappaB signaling pathway

“…FAK is a member of the focal adhesions that mediates integrin-mediated signal transduction associated with a variety of cellular functions including cellular proliferation, migration, and adhesion. The downstream signaling pathways involved in FAK signaling include the Jun N-terminal kinases (JNK) survival pathway, and the phosphoinositide 3-kinase (PI3K)/Akt pathway [ 17 ]. PI3K/Akt controls cell proliferation, survival, and apoptosis.…”

MicroRNA-133b/EGFR axis regulates esophageal squamous cell carcinoma metastases by suppressing anoikis resistance and anchorage-independent growth

“…ITGB4 has been suggested to be up-regulated in multiple tumors and contribute to tumor progression by promoting proliferation, invasion and EMT process [ 41 , 42 ]. A previous study showed that ITGB4 affected anoikis through interacting with EGFR in hepatocellular carcinoma [ 25 ]. ITGB4 was found to trigger the activation of downstream transmembrane protein kinases, including FAK, to protect against anoikis [ 43 ].…”

“…ITGB4 belongs to the integrin family and has been reported to influence carcinoma progression via modulating anoikis. Focal adhesion kinase (FAK) is a protein tyrosine kinase that mediates cell adhesion, and the activation of FAK can ligate conformation of integrin to promote cell proliferation via downstream phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT) pathway, which finally lead to anoikis resistance [ 25 ]. Growth factor receptor-bound protein 2 (Grb2) is a member of integrin adhesive and critical for the malignant progression of tumors [ 26 ].…”

Integrin as a Molecular Target for Anti-cancer Approaches in Lung Cancer

“…Treatment of the MCF-7 cancer cells with this lectin resulted in the depletion of integrin levels followed by the decrease of active FAK and active Ras. As a consequence, the lack of integrin-mediated cell survival signals sensitized the cell to anoikis (48).…”