title: The intrinsically kinase-inactive EPHB6 receptor predisposes cancer cells to DR5-induced apoptosis by promoting mitochondrial fragmentation.
abstract: Death Receptor 5 (DR5) is a promising target for cancer therapy due to its ability to selectively induce apoptosis in cancer cells. However, the therapeutic usefulness of DR5 agonists is currently limited by the frequent resistance of malignant tumours to its activation. The identification of molecular mechanisms that determine outcomes of DR5 action is therefore crucial for improving the efficiency of DR5-activating reagents in cancer treatment. Here, we provide evidence that an intrinsically kinase-inactive member of the Eph group of receptor tyrosine kinases, EPHB6, induces marked fragmentation of the mitochondrial network in breast cancer cells of triple-negative origin, lacking expression of the estrogen, progesterone and HER2 receptors. Remarkably, this response renders cancer cells more susceptible to DR5-mediated apoptosis. EPHB6 action in mitochondrial fragmentation proved to depend on its ability to activate the ERK-DRP1 pathway, which increases the frequency of organelle fission. Moreover, DRP1 activity is also essential to the EPHB6-mediated pro-apoptotic response that we observe in the context of DR5 activation. These findings provide the first description of a member of the receptor tyrosine kinase family capable of producing a pro-apoptotic effect through the activation of ERK-DRP1 signaling and subsequent mitochondrial fragmentation. Our observations are of potential practical importance, as they imply that DR5-activating therapeutic approaches should be applied in a more personalized manner to primarily treat EPHB6-expressing tumours. Finally, our findings also suggest that the EPHB6 receptor itself may represent a promising target for cancer therapy, since EPHB6 and DR5 co-activation should support more efficient elimination of cancer cells.
authors: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.|Faculty of Science, Damanhour University, Damanhour, 22516, Egypt.
authors: Amr M
authors: AM
authors: El Zawily
authors: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors: Behzad M
authors: BM
authors: Toosi
authors: Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada.
authors: Tanya
authors: T
authors: Freywald
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
authors: Vijaya V
authors: VV
authors: Indukuri
authors: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.|Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada.
authors: Franco J
authors: FJ
authors: Vizeacoumar
authors: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
authors: Scot C
authors: SC
authors: Leary
authors: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors: Andrew
authors: A
authors: Freywald
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C106797:EPHB6 protein, human; D036081:Receptors, Eph Family; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: DR5; DRP1; EPHB6; cancer; mitochondrial dynamics