Integrin-linked kinase regulates senescence in an Rb-dependent manner in cancer cell lines

Abstract

Anti-integrin-linked kinase (ILK) therapies result in aberrant mitosis including altered mitotic spindle organization, centrosome declustering and mitotic arrest. In contrast to cells that expressed the retinoblastoma tumor suppressor protein Rb, we have shown that in retinoblastoma cell lines that do not express Rb, anti-ILK therapies induced aberrant mitosis that led to the accumulation of temporarily viable multinucleated cells. The present work was undertaken to: 1) determine the ultimate fate of cells that had survived anti-ILK therapies and 2) determine whether or not Rb expression altered the outcome of these cells. Our data indicate that ILK, a chemotherapy drug target is expressed in both welldifferentiated, Rb-negative and relatively undifferentiated, Rb-positive retinoblastoma tissue. We show that small molecule targeting of ILK in Rb-positive and Rb-deficient cancer cells results in increased centrosomal declustering, aberrant mitotic spindle formation and multinucleation. However, anti-ILK therapies in vitro have different outcomes in retinoblastoma and glioblastoma cell lines that depend on Rb expression. TUNEL labeling and propidium iodide FACS analysis indicate that Rb-positive cells exposed to anti-ILK therapies are more susceptible to apoptosis and senescence than their Rb-deficient counterparts wherein aberrant mitosis induced by anti-ILK therapies exhibit mitotic arrest instead. These studies are the first to show a role for ILK in chemotherapy-induced senescence in Rb-positive cancer lines. Taken together these results indicate that the oncosuppressive outcomes for anti-ILK therapies in vitro, depend on the expression of the tumor suppressor Rb, a known G 1 checkpoint and senescence regulator.

Bufalin enhances antitumor effect of paclitaxel on cervical tumorigenesis via inhibiting the integrin α2/β5/FAK signaling pathway

“…Integrins are heterodimeric cell adhesion receptors, which contain two different chains, α and β subunits [ 13 ]. Integrins mediate a wide variety of cell-cell and cell-matrix interactions that lead to cell migration, proliferation, differentiation and survival [ 14 - 16 ], by modulating the cell signaling pathways of transmembrane protein kinases such as Focal Adhesion Kinase (FAK) [ 17 , 18 ]. Integrin/FAK signal pathway participates in the activation of akt and the inhibition of GSK3β, and then promotes tumorigenesis, cell metastasis and chemoresistance [ 19 - 21 ].…”

Expression Profile and Function Analysis of LncRNAs during Priming Phase of Rat Liver Regeneration

“…Jiao et al stated that in response to tissue injury, cytokines and chemokines are stimulated, which result in the activation of some downstream transcription factors (TFs) including nuclear factor-κB (NF-κB), activator protein 1 (AP-1), signal transducers and transcription activators 3 (STAT3) and CCAAT enhancer-binding protein (C/EBP), and a large number of genes including promitogenic genes and homeostatic response genes [ 21 ]. Previous research asserted that hepatocytes were activated at 2 h of LR after PH, and their transition from G0 phase to cell cycle occurred at 2–6 h [ 43 ] ILK pathway could activate the nuclear translocation of β-catenin and enhanced the transcription of LEF-1 through integrin-linked kinase pathway, and then increase the activity of Ap-1 which could promote cell proliferation [ 44 , 45 ], and the expression of critical cytokine IL-6 [ 46 , 47 ] which could affect cell proliferation via Stat3 signal pathway. It has demonstrated that transforming growth factor-β (TGF-β) signaling plays a key role in progression and metastasis of HCC [ 48 , 49 ], and it influences the expression of smad4, smad2/3, and β-catenin proteins and regulates cell activities [ 49 ], which indicates that it is important in liver cells.…”

Loukoumasomes Are Distinct Subcellular Structures from Rods and Rings and Are Structurally Associated with MAP2 and the Nuclear Envelope in Retinal Cells

“…Human retinoblastoma cell lines (Y79 and Weri-Rb27) and R28 cells were cultured using DMEM+Glutamax (GIBCO), with 10% fetal bovine serum and gentamicin (50 μg/ml) as described. [48, 49] R28 cells were passaged onto poly-D-lysine coated coverslips in 6-well plates prior to ribavirin exposure at a density of 6.0×10 5 cells per well. Cells were incubated at 37°C and 5% CO 2 .…”