Melike Demir1, Onur Cizmecioglu1. 1. Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
Abstract
BACKGROUND/AIM: Tyrosine kinases have crucial functions in cell signaling and proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway is frequently deregulated in human cancer and is an essential regulator of cellular proliferation. We aimed to determine which tyrosine kinases contribute to resistance elicited by PI3K silencing and inhibition. MATERIALS AND METHODS: To mimic catalytic inactivation of p110α/β, specific p110α (BYL719) and p110β (KIN193) inhibitors were used in addition to genetic knock-out in in vitro assays. Cell viability was assessed using crystal violet staining, whereas cellular transformation ability was analyzed by soft-agar growth assays. RESULTS: Activated zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) generated resistance to PI3K inhibition. This resistance was via activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) axis. We demonstrated that activated ZAP70 has a high transforming capability associated with the formation of malignant phenotype in untransformed cells and has the potential to be a tumor-initiating factor in cancer cells. CONCLUSION: ZAP70 may be a potent driver of proliferation and transformation in untransformed cells and is implicated in resistance to PI3K inhibitors in cancer cells. Copyright 2022, International Institute of Anticancer Research.
BACKGROUND/AIM: Tyrosine kinases have crucial functions in cell signaling and proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway is frequently deregulated in human cancer and is an essential regulator of cellular proliferation. We aimed to determine which tyrosine kinases contribute to resistance elicited by PI3K silencing and inhibition. MATERIALS AND METHODS: To mimic catalytic inactivation of p110α/β, specific p110α (BYL719) and p110β (KIN193) inhibitors were used in addition to genetic knock-out in in vitro assays. Cell viability was assessed using crystal violet staining, whereas cellular transformation ability was analyzed by soft-agar growth assays. RESULTS: Activated zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) generated resistance to PI3K inhibition. This resistance was via activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) axis. We demonstrated that activated ZAP70 has a high transforming capability associated with the formation of malignant phenotype in untransformed cells and has the potential to be a tumor-initiating factor in cancer cells. CONCLUSION: ZAP70 may be a potent driver of proliferation and transformation in untransformed cells and is implicated in resistance to PI3K inhibitors in cancer cells. Copyright 2022, International Institute of Anticancer Research.
Authors: Dejan Juric; Jordi Rodon; Josep Tabernero; Filip Janku; Howard A Burris; Jan H M Schellens; Mark R Middleton; Jordan Berlin; Martin Schuler; Marta Gil-Martin; Hope S Rugo; Ruth Seggewiss-Bernhardt; Alan Huang; Douglas Bootle; David Demanse; Lars Blumenstein; Christina Coughlin; Cornelia Quadt; José Baselga Journal: J Clin Oncol Date: 2018-02-05 Impact factor: 44.544