Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway

Yarangsee, Piimwara; Fukai, Itsuki; Phol, Sophany; Kinugawa, Kosei; Kusagawa, Eiichi; Miyake, Yasunobu; Kataoka, Takao

doi:10.3390/ijms27115011

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Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway

by

Piimwara Yarangsee

¹,

Itsuki Fukai

¹,

Sophany Phol

¹,

Kosei Kinugawa

¹,

Eiichi Kusagawa

¹,

Yasunobu Miyake

²

and

Takao Kataoka

^1,3,*

¹

Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan

²

Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga 849-8501, Japan

³

Center for Social and Biomedical Engineering, Kyoto Institute of Technology, Kyoto 606-8585, Japan

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(11), 5011; https://doi.org/10.3390/ijms27115011

Submission received: 27 January 2026 / Revised: 22 May 2026 / Accepted: 29 May 2026 / Published: 1 June 2026

(This article belongs to the Special Issue Anti-Cancer, Anti-Inflammatory, and Antioxidation Active Substances: 3rd Edition)

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Abstract

Cucurbitacin B belongs to a group of tetracyclic triterpenoids and exerts a number of biological effects, including anti-inflammatory and anticancer activities. We previously demonstrated that cucurbitacin B down-regulated tumor necrosis factor (TNF) receptor 1 (TNF-R1) expression and prevented activation of the transcription factor nuclear factor κB in response to a TNF-α stimulation. The present study shows that cucurbitacin B promoted the ectodomain shedding of TNF-R1 by generating a soluble form that accumulated in the culture medium of human lung adenocarcinoma A549 cells. Of the eight tetracyclic and pentacyclic triterpenoids consisting of an α,β-unsaturated carbonyl group that were examined, only cucurbitacin B promoted TNF-R1 ectodomain shedding. Cucurbitacin B-induced TNF-R1 shedding was attenuated by TNF-α protease inhibitor 2 and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, but not by the p38 MAPK inhibitor SB203580 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Consistent with these results, cucurbitacin B promoted the rapid phosphorylation of rapidly accelerated fibrosarcoma 1 (RAF1) and ERK, but exerted minimal effects on the phosphorylation of p38 MAPK and JNK. Collectively, these results demonstrate that cucurbitacin B selectively activated the RAF1-MEK-ERK pathway, which was essential for TNF-R1 ectodomain shedding.

Keywords: cucurbitacin B; triterpenoid; TNF receptor 1; shedding; ADAM; ERK; RAF1; MAPK; NF-κB

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MDPI and ACS Style

Yarangsee, P.; Fukai, I.; Phol, S.; Kinugawa, K.; Kusagawa, E.; Miyake, Y.; Kataoka, T. Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway. Int. J. Mol. Sci. 2026, 27, 5011. https://doi.org/10.3390/ijms27115011

AMA Style

Yarangsee P, Fukai I, Phol S, Kinugawa K, Kusagawa E, Miyake Y, Kataoka T. Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway. International Journal of Molecular Sciences. 2026; 27(11):5011. https://doi.org/10.3390/ijms27115011

Chicago/Turabian Style

Yarangsee, Piimwara, Itsuki Fukai, Sophany Phol, Kosei Kinugawa, Eiichi Kusagawa, Yasunobu Miyake, and Takao Kataoka. 2026. "Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway" International Journal of Molecular Sciences 27, no. 11: 5011. https://doi.org/10.3390/ijms27115011

APA Style

Yarangsee, P., Fukai, I., Phol, S., Kinugawa, K., Kusagawa, E., Miyake, Y., & Kataoka, T. (2026). Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway. International Journal of Molecular Sciences, 27(11), 5011. https://doi.org/10.3390/ijms27115011

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Cucurbitacin B Promotes Tumor Necrosis Factor Receptor 1 Ectodomain Shedding by Selectively Activating the Extracellular Signal-Regulated Kinase Signaling Pathway

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