βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer
Author:
Kokkinos JohnORCID, Sharbeen GeorgeORCID, Ignacio Rosa Mistica C., Pandzic Elvis, Youkhana Janet, Boyer Cyrille, Haghighi Koroush S., Gunawarman Matthew, Goldstein David, Gebski Val, Pajic Marina, Pitiyarachchi Omali, Davis Meagan E., Schulstad Grace, Arkell Oliver S.M., Kopecky Chantal, Gonzales-Aloy Estrella, Erkan Mert, Morton Jennifer P., Kavallaris Maria, Gunning Peter W.ORCID, Hardeman Edna C., Johns Amber, Gill Anthony J., Whan Renee M., Mawson Amanda, McCarroll Joshua A.ORCID, Phillips Phoebe A.ORCID,
Abstract
AbstractThe microtubule protein, βIII-tubulin, has been implicated as a prognostic, pro-survival, and chemoresistance factor in some of the most lethal malignancies including pancreatic ductal adenocarcinoma (PDAC). However, precise survival mechanisms controlled by βIII-tubulin in cancer cells are unknown. Here, we report an unexpected role of βIII-tubulin as a brake on extrinsic caspase 8-dependent apoptosis in PDAC. We show that βIII-tubulin knockdown frees death-receptor DR5 to increase its membrane diffusion, clustering, and activation of cell-death. We demonstrate that βIII-ubulin silencing increases sensitivity of PDAC cells to chemotherapeutic and microenvironment-derived extrinsic cell-death signals including TRAIL, TNFα, and FasL. Finally, nanoparticle delivery of βIII-tubulin siRNA to mouse orthotopic PDAC tumours in vivo and human patient-derived PDAC tumour explants ex vivo increases extrinsic apoptosis and reduces tumour progression. Thus, silencing of βIII-tubulin represents an innovative strategy to unleash a suicide signal in PDAC cells and render them sensitive to microenvironment and chemotherapy-derived death signals.
Publisher
Cold Spring Harbor Laboratory
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