Viral G protein-coupled receptors as modulators of cancer hallmarks
Jeffrey R van Senten1, Tian Shu Fan1, Marco Siderius1
1Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
Abstract:
Herpesviruses encode transmembrane G protein-coupled receptors (GPCRs), which share structural homology to human chemokine receptors. These viral GPCRs include KSHV-encoded ORF74, EBV-encoded BILF1, and HCMV-encoded US28, UL33, UL78 and US27. Viral GPCRs hijack various signaling pathways and cellular networks, including pathways involved in the so-called cancer hallmarks as defined by Hanahan and Weinberg. These hallmarks describe cellular characteristics crucial for transformation and tumor progression. The cancer hallmarks involve growth factor-independent proliferation, angiogenesis, avoidance of apoptosis, invasion and metastasis, metabolic reprogramming, genetic instability and immune evasion amongst others. The role of beta herpesviruses modulating these cancer hallmarks is clearly highlighted by the proliferative and pro-angiogenic phenotype associated with KSHV infection which is largely ascribed to the ORF74-mediated modulation of signaling networks in host cells. For HCMV and Epstein-Bar encoded GPCRs, oncomodulatory effects have been described which contribute to the cancer hallmarks, thereby enhancing oncogenic development. In this review, we describe the main signaling pathways controlling the hallmarks of cancer which are affected by the betaherpesvirus encoded GPCRs. Most prominent among these involve the JAK-STAT, PI(3)K-AKT, NFkB and MAPK signaling nodes. These insights are important to effectively target these viral GPCRs and their signaling networks in betaherpesvirus-associated malignancies.
Insights
Beta herpesviruses encode G protein-coupled receptors (GPCRs) that manipulate cancer hallmarks. Targeting these viral GPCRs and their signaling pathways offers a strategy against virus-associated cancers.
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- Herpesviruses encode G protein-coupled receptors (GPCRs) homologous to human chemokine receptors.
- Viral GPCRs, including KSHV ORF74, EBV BILF1, and HCMV US28/UL33/UL78/US27, interact with host cell pathways.
Purpose of the Study:
- To review how beta herpesvirus-encoded GPCRs modulate the hallmarks of cancer.
- To highlight key signaling pathways targeted by these viral GPCRs.
Main Methods:
- Literature review of studies on viral GPCRs and cancer hallmarks.
- Analysis of signaling pathways affected by viral GPCRs, such as JAK-STAT, PI(3)K-AKT, NFkB, and MAPK.
Main Results:
- Viral GPCRs contribute to cancer hallmarks like proliferation, angiogenesis, and immune evasion.
- KSHV ORF74 drives a proliferative and pro-angiogenic phenotype.
- HCMV and EBV GPCRs exhibit oncomodulatory effects.
Conclusions:
- Beta herpesvirus GPCRs significantly impact cancer development by hijacking host signaling pathways.
- Understanding these viral GPCRs and their associated signaling networks is crucial for developing targeted therapies against virus-associated malignancies.
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