Villejuif, France
Villejuif, France
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Criollo A.,INSE RM | Criollo A.,Institute Gustave Roussy | Criollo A.,University Paris - Sud | Chereau F.,Institute Cochin | And 23 more authors.
Cell Cycle | Year: 2012

It is well established that the activation of the inhibitor of NFκB (IκBα) kinase (IKK) complex is required for autophagy induction by multiple stimuli. Here, we show that - in autophagy-competent mouse embryonic fibroblasts (MEFs) - distinct autophagic triggers including starvation, mTOR inhibition with rapamycin and p53 inhibition with cyclic pifithrin α lead to the activation of IKK, followed by the phosphorylation-dependent degradation of IκBα and nuclear translocation of NFκB. Remarkably, the NFκB signaling pathway was blocked in MEFs lacking either the essential autophagy genes Atg5 or Atg7. In addition, we found that tumor necrosis factor α (TNFα)-induced NFκB nuclear translocation is abolished in both Atg5- and Atg7-deficient MEFs. Similarly, the depletion of essential autophagy modulators including ATG5, ATG7, Beclin 1 and VPS34 by RNA interference inhibited TNFα-driven NFκB activation in two human cancer cell lines. In conclusion, it appears that, at least in some instances, autophagy is required for NFκB activation, highlighting an intimate crosstalk between these two stress response signaling pathways. © 2012 Landes Bioscience.

Ma Y.,INSE RM | Ma Y.,Institute Gustave Roussy | Ma Y.,University Paris - Sud | Yamazaki T.,Institute Gustave Roussy | And 15 more authors.
OncoImmunology | Year: 2013

The antineoplastic effects of anthracyclines have been shown to rely, at least in part, on a local immune response that involves dendritic cells (DCs) and several distinct subsets of T lymphocytes. Here, we show that the administration of anthracyclines to mice bearing established neoplasms stimulates the intratumoral secretion of tumor necrosis factor a (TNF α). However, blocking the TNF α/TNF receptor (TNFR) system by three different strategies-namely, (1) neutralizing antibodies, (2) etanercept, a recombinant protein in which TNFR is fused to the constant domain of an IgG1 molecule, and (3) gene knockout-failed to negatively affect the therapeutic efficacy of anthracyclines in three distinct tumor models. In particular, TNF α-blocking strategies did not influence the antineoplastic effects of doxorubicin (a prototypic anthracycline) against MCA 205 fibrosarcomas growing in C57BL/6 mice, F244 sarcomas developing in 129/Sv hosts and H2N100 mammary carcinomas arising in BALB/c mice. These findings imply that, in contrast to other cytokines (such as interleukin-1β, interleukin-17 and interferon γ), TNFαis not required for anthracyclines to elicit therapeutic anticancer immune responses. © 2013 Landes Bioscience.

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