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

Abstract

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.

MAEL contributes to gastric cancer progression by promoting ILKAP degradation

“…ILKAP is a member of the PP2C phosphatase family. It functions as a tumor suppressor [ 27 , 29 , 30 ], is down-regulated in malignant melanoma [ 31 ] and is deleted in oral cancer [ 32 ]. Based on our findings, MAEL overexpression contributes to the depression of ILKAP in gastric cancer.…”

Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update

“…The anti-apoptotic survivin, induced by irradiation [ 100 ], can also modulate the radiotherapy-induced mitotic U87 cell death through an ILK/HIF-1α/survivin pathway [ 101 ]. Besides ILK/FAK, other focal adhesion proteins such as PINCH1 and ILKAP contribute to GB radioresistance [ 102 ]. Among potential mechanisms in GB, integrins could also act by cell cycle modulation [ 103 ], since irradiation-induced cell cycle arrest is potentiated by α6β4/laminin-5 adhesion in prostate cancer [ 104 ].…”

SuperQuant-assisted comparative proteome analysis of glioblastoma subpopulations allows for identification of potential novel therapeutic targets and cell markers

“…Since GBM recurrence after treatment is thought to be due to CSCs [ 6 ], our data suggest that inhibition of ILK signaling can be a potential treatment for GBM. In fact, a recent study has shown that p53-wildtype GBM cells were more susceptible to radiotherapy after the knockdown of ILK and its signaling partners PINCH1 and ILKAP [ 24 ].…”