title: Persistent inhibition of ABL tyrosine kinase causes enhanced apoptotic response to TRAIL and disrupts the pro-apoptotic effect of chloroquine.
abstract: TNF-Related Apoptosis Inducing Ligand (TRAIL) binds to and activates death receptors to stimulate caspase-8 and apoptosis with higher efficiency in cancer than normal cells but the development of apoptosis resistance has limited its clinical efficacy. We found that stable, but not transient knockdown of the ABL tyrosine kinase enhanced the apoptotic response to TRAIL. Re-expression of Abl, but not its nuclear import- or kinase-defective mutant, in the ABL-knockdown cells re-established apoptosis suppression. TRAIL is known to stimulate caspase-8 ubiquitination (Ub-C8), which can facilitate caspase-8 activation or degradation by the lysosomes. In the ABL-knockdown cells, we found a higher basal level of Ub-C8 that was not further increased by lysosomal inhibition. Re-expression of Abl in the ABL-knockdown cells reduced the basal Ub-C8, correlating with apoptosis suppression. We found that lysosomal inhibition by chloroquine (CQ) could also enhance TRAIL-induced apoptosis. However, this pro-apoptotic effect of CQ was lost in the ABL-knockdown cells but restored by Abl re-expression. Interestingly, kinase inhibition at the time of TRAIL stimulation was not sufficient to enhance apoptosis. Instead, persistent treatment for several days with imatinib, an ABL kinase inhibitor, was required to cause the enhanced and the CQ-insensitive apoptotic response to TRAIL. Together, these results show that persistent loss of nuclear ABL tyrosine kinase function can sensitize cells to TRAIL and suggest that long-term exposure to the FDA-approved ABL kinase inhibitors may potentiate apoptotic response to TRAIL-based cancer therapy.
authors.affiliation: Moores Cancer Center, Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Priya
authors.initials: P
authors.lastname: Sridevi
authors.forename: May K
authors.initials: MK
authors.lastname: Nhiayi
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Setten
authors.forename: Jean Y J
authors.initials: JY
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology*; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D054875:Ubiquitination
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; D002738:Chloroquine; D016315:Proto-Oncogene Proteins c-abl; D053181:Caspase 8