Abstract
The MAGE-A, MAGE-B, and MAGE-C protein families comprise the class-I MAGE/cancer testes antigens, a group of highly homologous proteins whose expression is suppressed in all normal tissues except developing sperm. Aberrant expression of class I MAGE proteins occurs in melanomas and many other malignancies, and MAGE proteins have long been recognized as tumor-specific targets; however, their functions have largely been unknown. Here, we show that suppression of class I MAGE proteins induces apoptosis in the Hs-294T, A375, and S91 MAGE-positive melanoma cell lines and that members of all three families of MAGE class I proteins form complexes with KAP1, a scaffolding protein that is known as a corepressor of p53 expression and function. In addition to inducing apoptosis, MAGE suppression decreases KAP1 complexing with p53, increases immunoreactive and acetylated p53, and activates a p53 responsive reporter gene. Suppression of class I MAGE proteins also induces apoptosis in MAGE-A-positive, p53wt/wt parental HCT 116 colon cancer cells but not in a MAGE-A-positive HCT 116 p53-/- variant, indicating that MAGE suppression of apoptosis requires p53. Finally, treatment with MAGE-specific small interfering RNA suppresses S91 melanoma growth in vivo, in syngenic DBA2 mice. Thus, class I MAGE protein expression may suppress apoptosis by suppressing p53 and may actively contribute to the development of malignancies and by promoting tumor survival. Because the expression of class I MAGE proteins is limited in normal tissues, inhibition of MAGE antigen expression or function represents a novel and specific treatment for melanoma and diverse malignancies.
Highlights
The cancer testes antigens are a group of proteins originally defined by their normal expression in testes and their aberrant expression in melanomas and other cancers
Working with human melanoma cell lines that express MAGE-A and MAGE-C2 proteins, and with a murine melanoma cell line that expresses mMage-b, we found that transfection with siRNAs targeting several MAGE genes decreased cell viability compared with the same cells transfected with control siRNA (Fig. 1)
We found that we could bring down KAP1 with endogenous MAGE-A using a pan-anti-MAGE-A antibody and that we could bring down V5-tagged human MAGE-A3 and V5-tagged murine mMage-b with KAP1 ( Fig. 3A)
Summary
The cancer testes antigens are a group of proteins originally defined by their normal expression in testes and their aberrant expression in melanomas and other cancers. MAGE gene expression can be caused by promoter region demethylation and is widespread in malignancies, being found in 50% or more of melanomas, synovial sarcomas, and primary carcinomas of the lung, head and neck, urinary bladder, and ovaries, as well as lesser percentages of primary breast carcinomas and myelomas [5,6,7,8] Despite their widespread expression, the functions of most class I MAGE molecules have not been determined, and it is not known whether their expression is a functionally irrelevant by-product of cellular transformation or could contribute to the development of malignancies [2]
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