The adherens junction-associated protein 1 is a negative transcriptional regulator of MAGEA2, which potentiates temozolomide-induced apoptosis in GBM.
Previous studies identified the frequent loss of adherens junction-associated protein 1 (AJAP1) expression in glioblastoma (GBM) and its correlation with worse survival. AJAP1 may suppress glioma cell migration, which plays an important role in tumor progression in malignant gliomas such as GBM. However, the role of AJAP1 in cell cycle arrest or apoptosis and resistance to chemotherapy remains unclear. Based on microarray screening results, quantitative PCR and luciferase plasmid reporter constructs were used to evaluate the possible regulatory role of AJAP1 on MAGEA2 expression and function. Cell death assays, TUNEL and other markers of apoptosis were utilized to detect cell apoptosis. Restoration of AJAP1 expression in glioma cells was analyzed after temozolomide exposure. AJAP1 suppressed the expression of MAGEA2 and inhibited the transcriptional activity of MAGEA2 in glioma cells. As AJAP1 expression decreased MAGEA2 protein expression apoptosis increased moderately. Consistent with increased cell death, the induced loss of MAGEA2 expression correlated with increased caspase 3/7 activity, BCL2/BAX ratio and TUNEL signal. AJAP1 expression enhanced cell death in the presence of temozolomide. This study suggests AJAP1 may also function as a pro-apoptotic factor and potentiate cell death by temozolomide in glioma cells. This effect may be partially explained by AJAP1-mediated gene regulation of MAGEA2.
Department of Neurosurgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China.
Liang
L
Zeng
Preston Robert Tisch Brain Tumor Center, Departments of Surgery and Neurobiology, Duke University Medical Center, Durham, NC, USA.
Chunsheng
C
Kang
Preston Robert Tisch Brain Tumor Center, Departments of Surgery and Neurobiology, Duke University Medical Center, Durham, NC, USA.
Chunhui
C
Di
Durham VA Medical Center, Durham, NC, USA.
Brian E
BE
Fee
Durham VA Medical Center, Durham, NC, USA.
Miriam
M
Rivas
Preston Robert Tisch Brain Tumor Center, Departments of Surgery and Neurobiology, Duke University Medical Center, Durham, NC, USA.
James
J
Lin
Durham VA Medical Center, Durham, NC, USA.
David Cory
DC
Adamson
D022005:Adherens Junctions; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D058950:Melanoma-Specific Antigens / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D000077204:Temozolomide; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D000099186:Histone Deacetylase 3
D018906:Antineoplastic Agents, Alkylating; D053148:Caspase 3; D053179:Caspase 7; D015815:Cell Adhesion Molecules; D003606:Dacarbazine; D006655:Histone Deacetylases; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000099186:Histone Deacetylase 3; C483313:AJAP1 protein, human; C574803:MageA2 protein, human