Ribozymes targeting serine/threonine kinase Akt1 sensitize cells to anticancer drugs.
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/PKBalpha, Akt2/PKBbeta and Akt3/PKBgamma. 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.
Yanagihara
Miyako
M
Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan.
Katano
Masayoshi
M
Takahashi-Sasaki
Noriko
N
Kimata
Kiyonori
K
Taira
Kazunari
K
Andoh
Toshiwo
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D016337:RNA, Catalytic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D016337:RNA, Catalytic; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt