Abstract
The serine/threonine kinase mTOR, the major sensor of cell growth along the PI3K/Akt pathway, can be activated by agents acting on microtubules. Damaged microtubules induce phosphorylation of the Bcl-2 protein and lower the threshold of programmed cell death, both of which are inhibited by rapamycin. In HEK293 cells expressing Akt mutants, the level of Bcl-2 phosphorylation and the threshold of apoptosis induced by taxol or by nocodazole are significantly modified. In cells expressing dominant-negative Akt (DN-Akt), Bcl-2 phosphorylation and p70S6KThr421/Ser424 phosphorylation induced by taxol or nocodazole were significantly enhanced as compared to cells expressing constitutively active Akt (CA-Akt) and inhibited by rapamycin. Moreover, DN-Akt cells were more sensitive to antitubule agents than CA-Akt cells. In nocodazole-treated HEK293 cells sorted according to cell cycle, the p70S6KThr421/Ser424 phosphorylation was associated to the G2/M fraction. More relevant, nocodazole inhibited, in a dose–response manner, mTOR phosphorylation at Ser2448. This activity, potentiated in DN-Akt cells, was not detectable in CA-Akt cells. Our results suggest that death signals originating from damaged microtubules in G2/M can compete with G1 survival pathways at the level of mTOR. These findings have implications for cancer therapy and drug resistance.
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Acknowledgements
We thank Dr J Chen for plasmids and critically reading the manuscript, Dr A Gulino for plasmids, Dr P Woodford for revision of the manuscript and E Fontanella for helpful FACS assistance. This work was supported by grants from AIRC, Fondazione CARIPLO, Milan, Italy; MIUR, CNR-Project Oncology, Rome, Italy.
LA and AC were supported by a fellowship from FIRC.
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Asnaghi, L., Calastretti, A., Bevilacqua, A. et al. Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene 23, 5781–5791 (2004). https://doi.org/10.1038/sj.onc.1207698
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DOI: https://doi.org/10.1038/sj.onc.1207698
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