Aberrant activation of Akt plays a pivotal role in
cancer development. ATM, a
protein deficient in patients with
ataxia-telangiectasia disease, is traditionally considered as a
nuclear protein kinase that functions as a signal transducer in response to DNA damage. It has recently been shown that ATM is also a cytoplasmic
protein that mediates the full activation of Akt in response to
insulin. Our study shows that a specific ATM inhibitor,
KU-55933, blocks the phosphorylation of Akt induced by
insulin and
insulin-like growth factor I in
cancer cells that exhibit abnormal Akt activity. Moreover,
KU-55933 inhibits
cancer cell proliferation by inducing G(1) cell cycle arrest. It does so through the downregulation of the synthesis of
cyclin D1, a
protein known to be elevated in a variety of
tumors. In addition,
KU-55933 treatment during serum
starvation triggers apoptosis in these
cancer cells. Our results suggest that
KU-55933 may be a novel chemotherapeutic agent targeting
cancer resistant to traditional
chemotherapy or
immunotherapy due to aberrant activation of Akt. Furthermore,
KU-55933 completely abrogates
rapamycin-induced feedback activation of Akt. Combination of
KU-55933 and
rapamycin not only induces apoptosis, which is not seen in
cancer cells treated only with
rapamycin, but also shows better efficacy in inhibiting
cancer cell proliferation than each
drug alone. Therefore, combining
KU-55933 with
rapamycin may provide a highly effective approach for improving
mammalian target of rapamycin-targeted anticancer
therapy that is currently hindered by
rapamycin-induced feedback activation of Akt.