4.3 Article

Growth factor receptor and beta 1 integrin signaling differentially regulate basal clonogenicity and radiation survival of fibroblasts via a modulation of cell cycling

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SPRINGER
DOI: 10.1007/s11626-022-00656-z

关键词

beta1 integrin; Growth factor receptor; Cell cycle; Ionizing radiation

资金

  1. Projekt DEAL

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This study investigates the crosstalk between β1 integrins and growth factor receptor signaling and its impact on cellular radiation response in fibroblasts. The results show that the cooperation between β1 integrins and growth factor receptors is essential for enhancing radiation-induced cell cycle arrest and improving clonogenic survival.
Cell adhesion to extracellular matrix proteins mediates resistance to radio- and chemotherapy by activating integrin signaling. In addition, mutual and cooperative interactions between integrin and growth factor receptor signaling contribute to the cellular radiation response. Here, we investigate to which extend the crosstalk between beta 1 integrins and growth factor receptor signaling determines the cellular radiation response of fibroblasts by assessing clonogenic survival and cell cycling. By utilizing growth factor signaling competent and either beta 1 integrin wildtype GD25 beta 1A fibroblasts or beta 1 integrin mutant, signaling incompetent GD25 beta 1B fibroblasts, we show basal clonogenic survival to depend on growth factor receptor but not integrin signaling. Our data further suggest the cooperation between beta 1 integrins and growth factor receptors to be critical for enhancing the radiation-induced G2/M cell cycle block leading to improved clonogenic radiation survival. By pharmacological inhibition of EGFR and PI3K, we additionally show that the essential contribution of EGFR signaling to radiogenic G2/M cell cycle arrest depends on the co-activation of the beta 1 integrin signaling axis, but occurs independent of PI3K. Taken together, elucidation of the signaling circuitry underlying the EGFR/beta 1 integrin crosstalk may support the development of advanced molecular targeted therapies for radiation oncology.

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