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Tyrphostin A9 attenuates glioblastoma growth by suppressing PYK2/EGFR-ERK signaling pathway

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Abstract

Purpose

Glioblastoma (GBM) is a fatal primary brain tumor with extremely poor clinical outcomes. The anticancer efficiency of tyrosine kinase inhibitors (TKIs) has been shown in GBM and other cancer, with limited therapeutic outcomes. In the current study, we aimed to investigate the clinical impact of active proline-rich tyrosine kinase-2 (PYK2) and epidermal growth factor receptor (EGFR) in GBM and evaluate its druggability by a synthetic TKI-Tyrphostin A9 (TYR A9).

Methods

The expression profile of PYK2 and EGFR in astrocytoma biopsies (n = 48) and GBM cell lines were evaluated through quantitative PCR, western blots, and immunohistochemistry. The clinical association of phospho-PYK2 and EGFR was analyzed with various clinicopathological features and the Kaplan–Meier survival curve. The phospho-PYK2 and EGFR druggability and subsequent anticancer efficacy of TYR A9 was evaluated in GBM cell lines and intracranial C6 glioma model.

Results

Our expression data revealed an increased phospho-PYK2, and EGFR expression aggravates astrocytoma malignancy and is associated with patients’ poor survival. The mRNA and protein correlation analysis showed a positive association between phospho-PYK2 and EGFR in GBM tissues. The in-vitro studies demonstrated that TYR A9 reduced GBM cell growth, cell migration, and induced apoptosis by attenuating PYK2/EGFR-ERK signaling. The in-vivo data showed TYR A9 treatment dramatically reduced glioma growth with augmented animal survival by repressing PYK2/EGFR-ERK signaling.

Conclusion

Altogether, this study report that increased phospho-PYK2 and EGFR expression in astrocytoma was associated with poor prognosis. The in-vitro and in-vivo evidence underlined translational implication of TYR A9 by suppressing PYK2/EGFR-ERK modulated signaling pathway.

Graphical abstract

The schematic diagram displayed proof of concept of the current study indicating activated PYK2 either through the Ca2+/Calmodulin-dependent protein kinase II (CAMKII) signaling pathway or autophosphorylation at Tyr402 induces association to the SH2 domain of c-Src that leads to c-Src activation. Activated c-Src in turn activates PYK2 at other tyrosine residues that recruit Grb2/SOS complex and trigger ERK½ activation. Besides, PYK2 interaction with c-Src acts as an upstream of EGFR transactivator that can activate the ERK½ signaling pathway, which induces cell proliferation and cell survival by increasing anti-apoptotic proteins or inhibiting pro-apoptotic proteins. TYR A9 treatment attenuate GBM cell proliferation and migration; and induce GBM cell death by inhibiting PYK2 and EGFR-induced ERK activation.

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Data availability

All data corresponding to this study is available in this paper or its supplementary files.

Abbreviations

GBM:

Glioblastoma

PYK2:

Proline-rich kinase-2

EGFR:

Epidermal growth factor receptor

TKI:

Tyrosine kinase inhibitor

TYR A9:

Tyrphostin A9

AO:

Acridine orange

EtBr:

Ethidium bromide

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Acknowledgements

The authors thank Dr. Satish I. from the Department of Pathology, Krishna Institute of Medical Sciences, India, for their help in the clinicopathological assessment.

Funding

The financial assistance to the lab from the Ministry of Science and Technology, DST- SERB Core grant, file No. CRG/2020/005021 and financial support to the University of Hyderabad-IoE by the Ministry of Education, Govt. of India (F11/9/2019-U3 (A). BUILDER-DBT-BT/INF/22/SP41176/2020 to the school of life Sciences. NY thanks, CSIR-UGC for student fellowship (S.No. 2061630688 Ref. No: 19/06/2016(i) EU-V).

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Contributions

NY and PPB designed the study. NY performed all experiments. NY, DB and PPB analyzed data. MP and SM surgically excised astrocytoma tumor and NY collected tumor biopsies and provided clinical information. SM and MP evaluate clinicopathological data. NY and DB prepared the manuscript. NY, DB and PPB finalized the manuscript. All authors read and approved its submission.

Corresponding author

Correspondence to Prakash Babu Phanithi.

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The use of clinical biopsies and clinicopathological information in the study was approved by the Institutional Ethics Committee (UH/IEC/2016/180), University of Hyderabad, India. All animal procedures followed the Institutional Animal Ethics Committee guidelines (UH/IAEC/PPB/2021-22/22) of the University of Hyderabad.

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Yadav, N., Babu, D., Madigubba, S. et al. Tyrphostin A9 attenuates glioblastoma growth by suppressing PYK2/EGFR-ERK signaling pathway. J Neurooncol 163, 675–692 (2023). https://doi.org/10.1007/s11060-023-04383-7

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