Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer.
To identify potential therapeutic targets for lung cancer, we performed semi-genome-wide shRNA screening combined with the utilization of genome-wide expression and copy number data. shRNA screening targeting 5043 genes in NCI-H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tomohiko
T
Kakumu
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mitsuo
http://orcid.org/0000-0001-5458-9576
M
Sato
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Daiki
D
Goto
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Toshio
T
Kato
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Naoyuki
N
Yogo
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Tetsunari
T
Hase
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Masahiro
M
Morise
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takayuki
T
Fukui
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kohei
K
Yokoi
Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Yoshitaka
Y
Sekido
Hamon Center for Therapeutic Oncology Research and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Luc
L
Girard
Hamon Center for Therapeutic Oncology Research and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
John D
JD
Minna
Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
Lauren A
LA
Byers
Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
John V
JV
Heymach
Department of Biomedical Informatics, Ohio State University, Columbus, Ohio, USA.
Kevin R
KR
Coombes
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Masashi
M
Kondo
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yoshinori
Y
Hasegawa
D000072283:A549 Cells; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
C465641:PSMA6 protein, human; D046988:Proteasome Endopeptidase Complex
Apoptosis; lung neoplasms; proteasome endopeptidase complex; small interfering RNA; spliceosomes