BetaIII-tubulin can act as a brake on extrinsic apoptosis in pancreatic cancer

25/04/202625/07/2026

AI Summary

βIII-tubulin suppresses caspase 8-mediated extrinsic apoptosis; silencing activates caspase 8, reducing PDAC cell viability and tumour growth in vitro and in vivo.
βIII-tubulin knockdown increases sensitivity to TRAIL, TNFα and FasL by promoting DR5 diffusion and clustering at the plasma membrane to induce extrinsic apoptosis.
Nanoparticle delivery of βIII-tubulin siRNA reduces PDAC tumour growth, enhances TRAIL responsiveness, and stromal βIII-tubulin predicts poorer overall survival.

TL;DR (AI Generated)

Silencing βIII-tubulin in PDAC cells activated caspase 8, leading to decreased cell viability and growth both in vitro and in vivo. βIII-tubulin knockdown also increased the sensitivity of PDAC cells to extrinsic cell death signals, including TNF-related apoptosis-inducing ligand (TRAIL), TNFα, and FasL.

Furthermore, we demonstrated that βIII-tubulin knockdown in PDAC cells, in the absence or presence of TRAIL, increased diffusion and clustering of the TRAIL death receptor DR5 at the cell membrane, inducing extrinsic apoptosis.

In patient-derived human PDAC explants, βIII-tubulin silencing reduced tumour cell frequency and improved sensitivity to TRAIL.

Basic summary

Cell Death Dis. 2026 Apr 24. doi: 10.1038/s41419-026-08657-6. Online ahead of print.

ABSTRACT

The microtubule protein βIII-tubulin is a prognostic, pro-survival, and chemoresistance factor in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the precise survival mechanisms controlled by βIII-tubulin in cancer remain unknown. Here, we discovered a link between βIII-tubulin and the activation of caspase 8-mediated extrinsic apoptosis. Silencing βIII-tubulin in PDAC cells activated caspase 8, leading to decreased cell viability and growth both in vitro and in vivo. βIII-tubulin knockdown also increased the sensitivity of PDAC cells to extrinsic cell death signals, including TNF-related apoptosis-inducing ligand (TRAIL), TNFα, and FasL. Furthermore, we demonstrated that βIII-tubulin knockdown in PDAC cells, in the absence or presence of TRAIL, increased diffusion and clustering of the TRAIL death receptor DR5 at the cell membrane, inducing extrinsic apoptosis. Nanoparticle delivery of βIII-tubulin siRNA to mouse PDAC tumours reduced tumour growth and increased responsiveness to TRAIL therapy. In patient-derived human PDAC explants, βIII-tubulin silencing reduced tumour cell frequency and improved sensitivity to TRAIL. Finally, we showed that high βIII-tubulin expression in the human PDAC stroma was independently prognostic for poor overall survival. Taken together, silencing βIII-tubulin represents an innovative strategy to activate a suicide signal in PDAC cells and render them more sensitive to microenvironment- and chemotherapy-derived death signals.

PMID:42031726 | DOI:10.1038/s41419-026-08657-6

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