IngentaConnect Ribozymes targeting serine/threonine kinase Akt1 sensitize cells ...

Authors: Yanagihara, Miyako¹; Katano, Masayoshi¹; Takahashi-Sasaki, Noriko¹; Kimata, Kiyonori¹; Taira, Kazunari²; Andoh, Toshiwo

Source: Cancer Science, Volume 96, Number 9, September 2005 , pp. 620-626(7)

Publisher: Blackwell Publishing

Abstract:

The serine/threonine kinase Akt is a key component of the cellular signaling pathway for survival and drug-resistance in cancer cells. In the present study we confirmed this view by expressing an antagonist of Akt, a dominant negative form of Akt, in HCT116 colon carcinoma cells and observing apoptosis induction in cells in which expression of the mutant protein had been induced. Three isoforms of Akt have been found: Akt1/PKB alpha

, Akt2/PKB bgr

and Akt3/PKB ggr

. However, the function of individual isoforms with respect to tumorigenicity and drug-resistance of cancer cells is largely unknown. We designed ribozymes targeting the Akt1 protein in mammalian cells. Our data indicate that Akt1 ribozymes downregulate Akt1 expression to less than half that of control cells. Downregulation of Akt1 expression appears to sensitize HEK293 and HeLa cells to typical chemotherapeutic agents. However, Akt1 ribozymes had little effect on the proliferative activity of the cells. Thus, Akt as a whole and even just the Akt1 isozyme is an excellent target for chemotherapy. We further suggest a synergistic effect for combination therapy targeting Akt and other vital molecules such as tubulins, topoisomerases and protein kinases. (Cancer Sci 2005; 96: 620 – 626)

Document Type: Research article

DOI: 10.1111/j.1349-7006.2005.00088.x

Affiliations: 1: Department of Bioinformatics, Faculty of Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577; and 2: Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Hongo, Tokyo 113-8656, Japan

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Ribozymes targeting serine/threonine kinase Akt1 sensitize cells to anticancer drugs