Dynamics simulations of hypoxia inducible factor-1 regulatory network in cancer using formal verification techniques - Research paper

Sep 21, 2026

Hypoxia-inducible factor-1 (HIF-1) is investigated as a therapeutic target in cancer by modeling the signaling dynamics of HIF-1 and its interlinked proteins, including VEGF, ERK, AKT, GLUT-1, β-catenin, C-MYC, OGT, and p53. A Rene Thomas qualitative modeling framework is used, and dynamic simulations in cyclic conditions indicate oscillations linked to homeostasis or stable recovery. Perturbations drive cancerous or pathogenic states, while VEGF overexpression activates ERK and GLUT-1 and promotes aggressive tumor growth. The work further suggests coordinated modulation of VEGF, ERK, and β-catenin and uses SimBiology to support targeted therapeutic strategies.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages19

Reading Time48 min

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Introduction

HIF-1 regulation under hypoxia

Dysregulation and disease relevance

TYPE Original Research PUBLISHED 07 November 2024 DOI 10.3389/fmolb.2024.1386930 OPEN ACCESS EDITED BY Valentina Audrito, Università del Piemonte Orientale, Italy REVIEWED BY Iram Murtaza, Quaid-i-Azam University, Pakistan Saba Munawar, University of Wisconsin-Madison, United States Abrar Ahmed, Punjab University, Pakistan *CORRESPONDENCE Ishrat Jabeen, [ishrat.jabeen@sines.nust.edu.pk](ishrat.jabeen@sines.nust.edu.pk) RECEIVED 16 February 2024 ACCEPTED 28 October 2024 PUBLISHED 07 November 2024 CITATION Azhar HMF, Saeed MT and Jabeen I (2024) Dynamics simulations of hypoxia inducible factor-1 regulatory network in cancer using formal verification techniques. Front. Mol. Biosci. 11:1386930 . doi: 10.3389/fmolb.2024.1386930 COPYRIGHT © 2024 Azhar, Saeed and Jabeen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Dynamics simulations of hypoxia inducible factor-1 regulatory network in cancer using formal verification techniques Hafiz Muhammad Faraz Azhar, Muhammad Tariq Saeed and Ishrat Jabeen* School of Interdisciplinary Engineering and Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan Hypoxia-inducible factor-1 (HIF-1) regulates cell growth, protein translation, metabolic pathways and therefore, has been advocated as a promising biological target for the therapeutic interventions against cancer. In general, hyperactivation of HIF-1 in cancer has been associated with increases in the expression of glucose transporter type-1 (GLUT-1) thus, enhancing glucose consumption and hyperactivating metabolic pathways. The collective behavior of GLUT-1 along with previously known key players AKT, OGT, and VEGF isnot fully characterized and lacks clarity of how glucose uptake through this pathway (HIF-1) probes the cancer progression. This study uses a Rene Thomas qualitative modeling framework to comprehend the signaling dynamics of HIF-1 and its interlinked proteins, including VEGF, ERK, AKT, GLUT-1, β-catenin, C-MYC, OGT, and p53 to elucidate the regulatory mechanistic of HIF-1 in cancer. Our dynamic model reveals that continuous activation of p53, β-catenin, and AKTin cyclic conditions, leads to oscillations representing homeostasis or a stable recovery state. Any deviation from this cycle results in a cancerous or pathogenic state. The model shows that overexpression of VEGF activates ERK and GLUT- 1, leads to more aggressive tumor growth in a cancerous state. Moreover, it is observed that collective modulation of VEGF, ERK, and β-catenin is required for therapeutic intervention because these genes enhance the expression of GLUT-1 and play a significant role in cancer progression and angiogenesis. Additionally, SimBiology simulation unveils dynamic molecular interactions, emphasizing the need for targeted therapeutics to effectively regulate VEGF and ERK concentrations to modulate cancer cell proliferation. KEYWORDS hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), oglycosylation transferase (OGT), glucose transporter-1 (GLUT-1), extracellular single regulated kinase (ERK), cellular myelocytomatosis oncogene (C-MYC) 1 Introduction Cancer cell growth is a fundamental biological process characterized by cell proliferation, and an increase in cellular mass typically occurs under stress conditions. This complex process is strictly regulated and relies on vital nutrients like lipids and nucleic acids to provide sufficient energy to synthesize new cellular components. Frontiers in Molecular Biosciences 01 [fronti

FAQs

What biological role does HIF-1 play in cancer according to the study?

HIF-1 regulates cell growth, protein translation, and metabolic pathways, and its hyperactivation in cancer increases GLUT-1 expression and glucose consumption.

Which modeling approach is used to study the HIF-1 regulatory network?

The study uses a Rene Thomas qualitative modeling framework to comprehend HIF-1 signaling dynamics and interactions among related proteins.

What do the simulations indicate about cyclic activation in the model?

Continuous activation of p53, β-catenin, and AKT under cyclic conditions produces oscillations representing homeostasis or stable recovery, while deviations lead to cancerous or pathogenic states.

Sep 21, 2026

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