Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro

Storch, Katja; Sagerer, Andre; Cordes, Nils

doi:10.3892/or.2015.3753

Cited by 15 publications

(14 citation statements)

References 28 publications

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“…These findings are likely due to differences in cell lines. Storch and colleagues had similar results when they examined PARP and caspase 3 in glioblastoma cell lines treated with FAK inhibition [35] . Four different ovarian cancer cell lines also had varying levels of PARP cleavage and caspase 3 activation with FAK inhibition [36] .…”

Section: Discussionmentioning

confidence: 70%

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Waters

Stafman

Garner

et al. 2016

Translational Oncology

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Despite the tremendous advances in the treatment of childhood solid tumors, rhabdomyosarcoma (RMS) continues to provide a therapeutic challenge. Children with metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumorigenesis. Signaling pathways both upstream and downstream to FAK have been found to be important in sarcoma tumorigenesis, leading us to hypothesize that FAK would be present in RMS and would impact cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric alveolar and embryonal RMS tumor specimens and cell lines. We also examined the effects of FAK inhibition upon two RMS cell lines utilizing parallel approaches including RNAi and small molecule inhibitors. FAK inhibition resulted in decreased cellular survival, invasion, and migration and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse RMS xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in RMS and may provide desperately needed novel therapeutic strategies for these difficult-to-treat tumors.

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Section: Discussionmentioning

confidence: 70%

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Waters

Stafman

Garner

et al. 2016

Translational Oncology

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“…The mother compound of MPAP, TAE226 has been previously reported to possess cytotoxic activity against cancer cells. However, TAE226 exhibited radiosensitizing effects on only two out of seven glioblastoma cell lines at 10 µM, and exhibited no such effects on lung, pancreatic, or colorectal cancer cells (27,28). Therefore, the advantages of MPAP are its lower IC 50 value against FAK than that of TAE226, as well as its radiosensitizing effect on lung cancer cells, which is not exhibited by TAE226.…”

Section: Discussionmentioning

confidence: 95%

Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

Jung

Kho

Song

et al. 2017

International Journal of Oncology

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Focal adhesion kinase 1 (FAK1) is known to promote tumor progression and metastasis by controlling cell movement, invasion, survival and the epithelial-to-mesenchymal transition in the tumor microenvironment. As recent reports imply that FAK1 is highly associated with tumor cell development and malignancy, the inhibition of FAK1 activity could be an effective therapeutic approach for inhibiting the growth and metastasis of tumor cells. In this study, we aimed to determine the effect of a novel synthetic FAK1 inhibitor 2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-N-methyl-benzamide, (MPAP) on lung cancer cells. MPAP suppressed cancer cell proliferation and the phosphorylation of FAK1. Combined treatment with MPAP and irradiation (IR) showed enhanced suppression of cancer cell proliferation in wild-type p53 cells and more intense suppression in p53-null cells. In addition, the combination treatment effectively induced G1 cell cycle arrest in a p53-independent manner. In an in vivo tumor xenograft mouse model, treatment with both MPAP and IR reduced tumor growth more than the treatment with IR or MPAP alone. Overall, these data demonstrate that the radiosensitizing effect of MPAP is mediated by the regulation of retinoblastoma protein (RB) phosphorylation in a p53-independent manner.

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“…Focal adhesion kinase (FAK), which is a central mediator of integrin signaling in several tumor entities [ 48 , 53 ], could play a significant role in this process. This hypothesis is supported by a recent study showing a radiosensitizing effect of pharmacological FAK inhibition in U138MG (p53-mutated), but not in A172 or U87MG (p53-wildtype) cells [ 54 ].…”

Section: Discussionmentioning

confidence: 57%

ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation

et al. 2015

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The prognosis is generally poor for patients suffering from glioblastoma multiforme (GBM) due to radiation and drug resistance. Prosurvival signaling originating from focal adhesion hubs essentially contributes to therapy resistance and tumor aggressiveness. As the underlying molecular mechanisms remain largely elusive, we addressed whether targeting of the focal adhesion proteins particularly interesting new cysteine-histidine-rich 1 (PINCH1), integrin-linked kinase (ILK) and ILK associated phosphatase (ILKAP) modulates GBM cell radioresistance. Intriguingly, PINCH1, ILK and ILKAP depletion sensitized p53-wildtype, but not p53-mutant, GBM cells to radiotherapy. Concomitantly, these cells showed inactivated Glycogen synthase kinase-3β (GSK3β) and reduced proliferation. For PINCH1 and ILKAP knockdown, elevated levels of radiation-induced γH2AX/53BP1-positive foci, as a marker for DNA double strand breaks, were observed. Mechanistically, we identified radiation-induced phosphorylation of DNA protein kinase (DNAPK), an important DNA repair protein, to be dependent on ILKAP. This interaction was fundamental to radiation survival of p53-wildtype GBM cells. Conclusively, our data suggest an essential role of PINCH1, ILK and ILKAP for the radioresistance of p53-wildtype GBM cells and provide evidence for DNAPK functioning as a central mediator of ILKAP signaling. Strategies for targeting focal adhesion proteins in combination with radiotherapy might be a promising approach for patients with GBM.

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Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro

Cited by 15 publications

References 28 publications

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Targeting Focal Adhesion Kinase Suppresses the Malignant Phenotype in Rhabdomyosarcoma Cells

Novel focal adhesion kinase 1 inhibitor sensitizes lung cancer cells to radiation in a p53-independent manner

ILKAP, ILK and PINCH1 control cell survival of p53-wildtype glioblastoma cells after irradiation

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