Depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation

Oncotarget. 2016 Feb 23;7(8):9513-24. doi: 10.18632/oncotarget.7069.

Abstract

Our previous study revealed that knockdown of CABYR-a/b increases the chemosensitivity of lung cancer cells through inactivation of Akt. Here, we demonstrated that depletion of CABYR-a/b significantly increased DR5 expression and sensitized lung cancer cells to TRAIL-induced apoptosis in vitro and/or in vivo. Importantly, treatment with AD5-10, a DR5-specific agonistic monoclonal antibody, was able to mimic TRAIL-induced apoptosis in CABYR-a/b-silenced cells. Strikingly, we identified that depletion of CABYR-a/b not only increased the expressions of p73 and DR5 but also decreased the phosphorylation of YAP S127. Loss- or gain-of-function studies of YAP and p73 revealed that double deletions of YAP and p73 effectively decreased the expression of DR5 and abolished TRAIL-induced apoptosis in CABYR-a/b knockdown cells. Conversely, the co-overexpression of YAP and p73 promoted the expression of DR5 and sensitized cells to TRAIL-induced apoptosis. Taken together, our results demonstrate that depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation.

Keywords: CABYR-a/b; DR5; TRAIL; YAP; lung cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / genetics*
  • Calcium-Binding Proteins / genetics*
  • Cell Line, Tumor
  • Female
  • Humans
  • Lung Neoplasms / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism*
  • Protein Isoforms / genetics
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / agonists
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription Factors
  • Tumor Protein p73 / genetics
  • Tumor Protein p73 / metabolism*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • CABYR protein, human
  • Calcium-Binding Proteins
  • Phosphoproteins
  • Protein Isoforms
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • TP73 protein, human
  • Transcription Factors
  • Tumor Protein p73
  • YAP-Signaling Proteins
  • YAP1 protein, human