Inhibition of FAK Signaling Elicits Lamin A/C-Associated Nuclear Deformity and Cellular Senescence

Abstract

Focal adhesion kinase (FAK) is a non-receptor kinase that facilitates tumor aggressiveness. The effects of FAK inhibition include arresting proliferation, limiting metastasis, and inhibiting angiogenesis. PF-573228 is an ATP-competitive inhibitor of FAK. Treating lung cancer cells with PF-573228 resulted in FAK inactivation and changes in the expressions of lamin A/C and nuclear deformity. Since lamin A/C downregulation or deficiency was associated with cellular senescence, the senescence-associated β-galactosidase (SA-β-gal) assay was used to investigate whether PF-573228 treatment drove cellular senescence, which showed more SA-β-gal-positive cells in culture. p53 is known to play a pivotal role in mediating the progression of cellular senescence, and the PF-573228-treated lung cancer cells resulted in a higher p53 expression level. Subsequently, the FAK depletion in lung cancer cells was employed to confirm the role of FAK inhibition on cellular senescence. FAK depletion and pharmacological inhibition of lung cancer cells elicited similar patterns of cellular senescence, lamin A/C downregulation, and p53 upregulation, implying that FAK signaling is associated with the expression of p53 and the maintenance of lamin A/C levels to shape regular nuclear morphology and manage anti-senescence. Conversely, FAK inactivation led to p53 upregulation, disorganization of the nuclear matrix, and consequently cellular senescence. Our data suggest a new FAK signaling pathway, in that abolishing FAK signaling can activate the senescence program in cells. Triggering cellular senescence could be a new therapeutic approach to limit tumor growth.

FAK Inhibition Induces Glioblastoma Cell Senescence-Like State through p62 and p27

“…FAK inhibitors reduce cell proliferation, induce apoptosis, and slow GBM growth in vitro [8] and in vivo [33]. Specifically, PF-573228 promotes proliferative arrest through decreased CyclinB1 and Lamin A/C, and induces cancer cell senescence [34]. The effects of PF-573228 in GBM cell proliferation were linked to increasing numbers of Ki67-negative cells and to the stabilization of p27, as a result of SKP2 downregulation [11,19,32].…”

The Effect of Terpenoid Natural Chinese Medicine Molecular Compound on Lung Cancer Treatment

“…Metastasis linked with tumor invasion is a very complex phenomenon; multiple molecules affect tumor invasion-metastasis behavior from different aspects. Cell adhesion molecules are the key molecules to maintain the tissue structure, and they are also the main molecules that affect cell adhesion and motility [ 54 ]. The extracellular matrix is the tissue barrier for cancer cell invasion and metastasis.…”

Lamin A/C: Function in Normal and Tumor Cells

“…It is thought that nestin helps stabilize lamin A/C in tumor cells, which helps protect them from undergoing senescence, resulting in a poorer prognosis [ 73 ]. Focal adhesion kinase (FAK) was also found to be involved in senescence in tumor cells as inactivating FAK in lung cancer cells leads to downregulation of lamin A/C and senescence [ 106 ].…”