Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis.
A variety of melanoma antigen A (MAGE-A) genes are commonly detected in non-small cell lung cancers. Their biological function is not well characterized but may involve the regulation of apoptosis and cell cycle progression. We hypothesized that MAGE-A4 is involved in the regulation of apoptosis. To investigate this, expression of MAGE-A was evaluated. MAGE-A4 was expressed in 48% of non-small cell lung carcinomas. Ninety percent of lung carcinomas expressing MAGE-A4 were classified as squamous cell carcinomas and 10% were adenocarcinomas. Tumor-free surrounding lung tissue was negative for MAGE-A4. A molecular clone of MAGE-A4 derived from human lung cancer was stably expressed in human embryonic kidney cells (293 cells) to evaluate effects on cell death. Overexpression of MAGE-A4 increased apoptosis as measured by the apoptotic index (P < 0.0001) and caspase-3 activity (P < 0.002). Exposure to 25 micromol/L etoposide, a chemotherapeutic agent, increased the apoptotic effect (P < 0.0001). Furthermore, we show that MAGE-A4 silencing using a small interfering RNA approach results in decreased caspase-3 activity in the squamous cell lung cancer cell line H1703 by 58% (P = 0.0027) and by 24% (P = 0.028) in 293/MAGE-A4 cells. These findings suggest that MAGE-A4 expression may promote tumor cell death, sensitize malignancies to apoptotic stimuli, such as chemotherapeutic agents, and therefore may represent a tumor suppressor protein.
Peikert
Tobias
T
Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. peikert.tobias@mayo.edu
Specks
Ulrich
U
Farver
Carol
C
Erzurum
Serpil C
SC
Comhair
Suzy A A
SA
D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003001:Cloning, Molecular; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D005047:Etoposide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases