Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes proliferation. These escaping cells experience reduced DNA damage and p21 activation. Cells surviving treatment are enriched for anti-apoptotic proteins, including Triap1. Increasing Triap1 levels allows cells to survive the first treatment with reduced DNA damage and lower levels of p21; accordingly, decreasing Triap1 re-sensitizes cells to nocodazole. We show that Triap1 upregulation leads to the retention of cytochrome c in the mitochondria, opposing the partial activation of caspases caused by nocodazole. In summary, our results point to a potential role of Triap1 upregulation in the emergence of resistance to drugs that induce prolonged mitotic arrest.

Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest / Pavani, Mattia; Chiroli, Elena; Cancrini, Camilla; Gross, Fridolin; Bonaiuti, Paolo; Villa, Stefano; Giavazzi, Fabio; Matafora, Vittoria; Bachi, Angela; Fava, Luca; Lischetti, Tiziana; Ciliberto, Andrea. - In: CELL REPORTS. - ISSN 2211-1247. - 42:3(2023), pp. 11221501-11221521. [10.1016/j.celrep.2023.112215]

Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest

Fava, Luca;
2023-01-01

Abstract

Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes proliferation. These escaping cells experience reduced DNA damage and p21 activation. Cells surviving treatment are enriched for anti-apoptotic proteins, including Triap1. Increasing Triap1 levels allows cells to survive the first treatment with reduced DNA damage and lower levels of p21; accordingly, decreasing Triap1 re-sensitizes cells to nocodazole. We show that Triap1 upregulation leads to the retention of cytochrome c in the mitochondria, opposing the partial activation of caspases caused by nocodazole. In summary, our results point to a potential role of Triap1 upregulation in the emergence of resistance to drugs that induce prolonged mitotic arrest.
2023
3
Pavani, Mattia; Chiroli, Elena; Cancrini, Camilla; Gross, Fridolin; Bonaiuti, Paolo; Villa, Stefano; Giavazzi, Fabio; Matafora, Vittoria; Bachi, Angela; Fava, Luca; Lischetti, Tiziana; Ciliberto, Andrea
Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest / Pavani, Mattia; Chiroli, Elena; Cancrini, Camilla; Gross, Fridolin; Bonaiuti, Paolo; Villa, Stefano; Giavazzi, Fabio; Matafora, Vittoria; Bachi, Angela; Fava, Luca; Lischetti, Tiziana; Ciliberto, Andrea. - In: CELL REPORTS. - ISSN 2211-1247. - 42:3(2023), pp. 11221501-11221521. [10.1016/j.celrep.2023.112215]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/372844
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