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