In vitro effects of gamma-secretase inhibition in HPV-positive and HPV-negative head and neck squamous cell carcinoma

Varatanovic, Sara; Maier, Tobias; Al-Gboore, Sega; Stoiber, Stefan; Kandathil, Sam A.; Quint, Clemens; Brennus, Charlotte; Heiduschka, Gregor; Kadletz-Wanke, Lorenz; Brkic, Faris F.

doi:10.1007/s10637-023-01334-x

Cited by 2 publications

(2 citation statements)

References 29 publications

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“…This indicates the dual nature of Notch in HNC—it can act both as a tumor suppressor and as an oncogene. Nevertheless, early research of Notch abrogation via gamma‐secretase inhibition in HNC cell lines shows antiproliferative, antimigratory, anticlonogenic, and proapoptotic effects, 149,150 so it would be interesting to see how this research could be expanded further.…”

Section: Notch Signalingmentioning

confidence: 99%

The effects of HPV oncoproteins on host communication networks: Therapeutic connotations

Skelin,

Luk,

Butorac

et al. 2023

Journal of Medical Virology

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Human papillomavirus (HPV) infections are a leading cause of viral‐induced malignancies worldwide, with a prominent association with cervical and head and neck cancers. The pivotal role of HPV oncoproteins, E5, E6, and E7, in manipulating cellular events, which contribute to viral pathogenesis in various ways, has been extensively documented. This article reviews the influence of HPV oncoproteins on cellular signaling pathways within the host cell, shedding light on the underlying molecular mechanisms. A comprehensive understanding of these molecular alterations is essential for the development of targeted therapies and strategies to combat HPV‐induced premalignancies and prevent their progress to cancer. Furthermore, this review underscores the intricate interplay between HPV oncoproteins and some of the most important cellular signaling pathways: Notch, Wnt/β‐catenin, MAPK, JAK/STAT, and PI3K AKT/mTOR. The treatment efficacies of the currently available inhibitors on these pathways in an HPV‐positive context are also discussed. This review also highlights the importance of continued research to advance our knowledge and enhance therapeutic interventions for HPV‐associated diseases.

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Section: Notch Signalingmentioning

confidence: 99%

The effects of HPV oncoproteins on host communication networks: Therapeutic connotations

Skelin,

Luk,

Butorac

et al. 2023

Journal of Medical Virology

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“…Here, we use CRE in combination with cisplatin to test the hypothesis that targeting both DNA damage response and Notch signaling may result in potentially synergistic effects. The functional and molecular relationship between Notch signaling and cisplatin resistance has been only poorly investigated thus far [20][21][22] and almost exclusively in routine two-dimensional monolayer cell cultures.…”

Section: Introductionmentioning

confidence: 99%

Optimization of a Three-Dimensional Culturing Method for Assessing the Impact of Cisplatin on Notch Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC)

Anameriç,

Czerwonka,

Nees

2023

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type, with cisplatin being a primary treatment approach. However, drug resistance and therapy failure pose a significant challenge, affecting nearly 50% of patients over time. This research had two aims: (1) to optimize a 3D cell-culture method for assessing the interplay between tumor cells and cancer-associated fibroblasts (CAFs) in vitro; and (2) to study how cisplatin impacts the Notch pathway, particularly considering the role of CAFs. Using our optimized “3D sheet model” approach, we tested two HNSCC cell lines with different cisplatin sensitivities and moderate, non-mutated NOTCH1 and -3 expressions. Combining cisplatin with a γ-secretase inhibitor (crenigacestat) increased sensitivity and induced cell death in the less sensitive cell line, while cisplatin alone was more effective in the moderately sensitive line and sensitivity decreased with the Notch inhibitor. Cisplatin boosted the expression of core Notch signaling proteins in 3D monocultures of both lines, which was counteracted by crenigacestat. In contrast, the presence of patient-derived CAFs mitigated effects and protected both cell lines from cisplatin toxicity. Elevated NOTCH1 and NOTCH3 protein levels were consistently correlated with reduced cisplatin sensitivity and increased cell survival. Additionally, the Notch ligand JAG2 had additional, protective effects reducing cell death from cisplatin exposure. In summary, we observed an inverse relationship between NOTCH1 and NOTCH3 levels and cisplatin responsiveness, overall protective effects by CAFs, and a potential link between JAG2 expression with tumor cell survival.

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In vitro effects of gamma-secretase inhibition in HPV-positive and HPV-negative head and neck squamous cell carcinoma

Cited by 2 publications

References 29 publications

The effects of HPV oncoproteins on host communication networks: Therapeutic connotations

The effects of HPV oncoproteins on host communication networks: Therapeutic connotations

Optimization of a Three-Dimensional Culturing Method for Assessing the Impact of Cisplatin on Notch Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC)

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