Brain Metastases Are Regulated by Immuno-Inflammatory Signaling Pathways Governed by Stat3, Mapk and Tumor Suppressor P53 Status: Possible Therapeutic Targets

Authors

Sabrina L. Zeller, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.
Eris Spirollari, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.
Alis J. Dicpinigaitis, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.
John V. Wainwright, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.
Simon J. Hanft, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.Follow
Chirag D. Gandhi, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A.Follow
Meena Jhanwar-Uniyal, Department of Neurosurgery, Westchester Medical Center/New York Medical College, Valhalla, NY, U.S.A. meena_jhanwar@nymc.edu.

Author Type(s)

Resident/Fellow, Student

DOI

10.21873/anticanres.16783

Journal Title

Anticancer Research

First Page

13

Last Page

22

Document Type

Article

Publication Date

1-1-2024

Department

Neurosurgery

Abstract

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53), pSTAT3, pERK1/2, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3 and pERK1/2 were expressed at tumor margins, whereas p53 and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

Recommended Citation

Zeller, S. L., Spirollari, E., Dicpinigaitis, A. J., Wainwright, J. V., Hanft, S. J., Gandhi, C. D., & Jhanwar-Uniyal, M. (2024). Brain Metastases Are Regulated by Immuno-Inflammatory Signaling Pathways Governed by Stat3, Mapk and Tumor Suppressor P53 Status: Possible Therapeutic Targets. Anticancer Research, 44 (1), 13-22. https://doi.org/10.21873/anticanres.16783