Regulatory effects of mammalian target of rapamycin-mediated signals in the generation of arsenic trioxide responses

Altman, JK. et al. 2008. Journal of Biological Chemistry. 283, 1992 - 2001

Speaker: Yu-Ting Kao (高毓婷)               Time: 13:00~14:00, Oct. 29, 2008

Commentator: 徐麗君 老師                 Place: Room 601

Abstract:

   Arsenic trioxide (As₂O₃) has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). Although its role as a potent inducer of apoptosis was well-known, the mechanisms that mediate such effects are not well understood (1). The Akt/mTOR cascade is an important signaling pathway that is activated by a variety of cellular signals, but the precise regulatory role of this pathway in response to the induction of As₂O₃ was unknown. To clarify the regulation of Akt/mTOR pathway after As₂O₃ treatment, the authors used the cells with targeted disruption of both the Akt1 and Akt2 genes, and found that the induction of arsenic trioxide-dependent apoptosis is strongly enhanced in the absence of these kinases, suggesting that Akt1/Akt2 are activated in a negative feedback regulatory manner to control generation of As₂O₃ responses. These effects are also enhanced in double knock-out cells for both isoforms of the p70 S6 kinase (S6k1/S6k2), a downstream effector of Akt and mTOR. On the contrary, As₂O₃-dependent induction of apoptosis is diminished in cells with targeted disruption of TSC2, a negative upstream effector of mTOR. By using primary hematopoietic progenitors from patients with acute myeloid leukemia, the authors also found that pharmacological inhibition of mTOR enhances the suppressive effects of arsenic trioxide on leukemic progenitor colony formation. Moreover, siRNA-mediated inhibition of expression of the translational repressor 4E-BP1, partially reverses the effects of As₂O₃. In conclusion, these data provide evidence for a key regulatory role of the Akt/mTOR pathway induction by As₂O₃, and suggest that targeting this signaling cascade may provide a novel therapeutic approach to enhance the anti-leukemic properties of As₂O₃.

Reference:

1. Dan Douer and Martin S. Tallanm.2005. Arsenic Trioxide: New clinical experience with and old medication in hematologic malignancies. Journal of Clinical Oncology 23:2396-2410.