The N-terminal common domain of simian virus 40 large T and small t antigens acts as a transformation suppressor of the HER-2/neu oncogene

Abstract

Overexpression of HER-2/neu (also known as c-erbB-2) proto-oncogene frequently occurs in many di erent types of human cancers, including ovarian carcinoma, and is known to enhance tumor metastasis and chemoresistance. Previous studies showed that inhibition of HER-2/neu expression by various agents, such as adenovirus E1A and simian virus 40 large T, can lead to suppression of tumorigenicity of HER-2/neu-overexpressing cancer cells. Here we report that T/t-common, which contains the N-terminal common domain of simian virus 40 large T and small t antigens, could speci®cally repress the HER-2/neu promoter. When the coding sequence of T/tcommon was stably transfected into the HER-2/neuoverexpressing human ovarian carcinoma SK-OV-3 cells, the expression of HER-2/neu was dramatically reduced by the expression of T/t-common. Accordingly the tumorigenic potential of these T/t-common-expressing clones, including the ability to grow anchorage-independently and the ability to induce tumor in nu/nu mice, was also drastically suppressed. Furthermore, when T/tcommon was transiently cotransfected with the activated genomic neu into NIH3T3 cells, the transforming activity of the latter was suppressed by T/t-common in soft-agarose microcolony formation assays. Taken together, these data suggest that T/t-common may act as a transformation suppressor of the HER-2/neu oncogene.

SV40 T/t-common polypeptide inhibits angiogenesis and growth of HER2-overexpressing human ovarian cancer

“…9,27,28 Previously, we reported that SV40 T/t-common polypeptide, which contains the Nterminal common domain of SV40 large T and small t antigens, has transcriptional repression activity 29 and can specifically inhibit HER2 expression in the HER2-overexpressing ovarian carcinoma cells. 30 These results suggest that T/t-common might have the ability to inhibit angiogenesis and tumor growth in HER2-overexpressing ovarian cancer. Here we report that T/t-common can inhibit the ability of HER2-overexpressing human ovarian cancer cells to induce angiogenesis.…”

SV40 T/t-Common Polypeptide Specifically Induces Apoptosis in Human Cancer Cells that Overexpress HER2/neu

“…Plasmids pRSV.3-BglII, pRSV-T/t-common, pCMVHER2WT, pcDNA3, pCMV-bcl2, and pCMV-1 were previously described (25,31). The plasmid pCMV-T/t-common was constructed by inserting the HindIII-XbaI fragment of pRSV-T/t-common, which contains T/t-common coding unit, into the corresponding sites of pcDNA3.1 (purchased from Invitrogen, Carlsbad, CA).…”

“…We also reported that T/t-common, through inhibition of HER2/neu, can suppress the tumorigenic potential of the HER2/ neu-overexpressing ovarian cancer cells (25). T/t-common has been shown to have strong transcriptional repressing activity (26) and express a biological activity equivalent to the NH 2 -terminal nonconserved domain and the conserved domain 1 of E1A (27).…”

“…T/t-common has been shown to have strong transcriptional repressing activity (26) and express a biological activity equivalent to the NH 2 -terminal nonconserved domain and the conserved domain 1 of E1A (27). Although T/t-common contains a dnaJ domain, which has been shown to be required for large T transformation of cells (23), it alone lacks transforming activity (25,28). Taken together, these data suggest that T/t-common may be safer than E1A and large T for the treatment of HER2/neu-overexpressing cancers.…”

“…In search for other viral proteins that can inhibit HER2/neu expression, we previously reported that SV40 T/t-common polypeptide, which contains the NH 2 -terminal common domain of SV40 large T and small t antigens, can specifically repress HER2/ neu expression in the HER2/neu-overexpressing ovarian carcinoma cells (25). We also reported that T/t-common, through inhibition of HER2/neu, can suppress the tumorigenic potential of the HER2/ neu-overexpressing ovarian cancer cells (25).…”