Akt inhibition improves irinotecan treatment and prevents cell emergence by switching the senescence response to apoptosis.
Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis.
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Alexandra
A
Vétillard
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Barbara
B
Jonchère
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Marie
M
Moreau
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Bertrand
B
Toutain
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Cécile
C
Henry
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Simon
S
Fontanel
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Anne-Charlotte
AC
Bernard
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Mario
M
Campone
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Catherine
C
Guette
Paul Papin ICO Cancer Center, INSERM U892, CNRS 6299, Angers University, Angers, France.
Olivier
O
Coqueret
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010069:Oxadiazoles / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C528328:GSK690693; D010069:Oxadiazoles; D000077146:Irinotecan; D051057:Proto-Oncogene Proteins c-akt; D002166:Camptothecin
Akt; chemotherapy; drug resistance; irinotecan; senescence