Drug Resistance and New Treatments, Montpellier – May 2016 CFATG
Drug Resistance and New Treatments, Montpellier – May 2016
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Team: Drug Resistance and New Treatments

Institut de Recherche en Cancérologie de Montpellier (U1194)
Campus Val d’Aurelle
34298 Montpellier cedex 5 FRANCE
Tel : 33.(0)4.67.61.85.77, Fax : 33.(0)4.67.61.37.87

Presentation of the team

Web site : http://www.ircm.fr/document.php?pagendx=391

Team leader: Céline Gongora, DR2 CNRS, celine.gongora@inserm.fr

Our team is composed of approximately 20 people including academic researchers and clinicians. Our project is centered on the mechanisms of action of chemotherapy and on the resistance to cancer treatments. We develop both research programs in vitro and in animal models, as well as integrated translational research in close cooperation with clinicians. We conduct a fundamental and cross-cutting research that should quickly benefit to the patient and one of our objectives is to study the role of autophagy in colon cancer and prostate cancer.

Principal Investigator :
Sophie Pattingre, CR1 INSERM, sophie.pattingre@inserm.fr

Autophagy Team members, 2016 :
Leïla El Kebriti, PhD student, first year
Céline Gongora, Group leader, DR2 CNRS
Nadine Houédé, PUPH, Chief of oncology department, CHU of Nîmes
Stéphane Obled, Gastroenterologist, Oncology department, CHU of Nîmes
Sophie Pattingre, CR1 INSERM
Esther Perez-Gracia, AI ICM (Institute of Cancer in Montpellier, France)

Pattingre team

Keywords:
Acetylation, cancer, signaling, resistance, metastasis

Research Topic

1- Regulation of autophagy by post-translational modifications (S. Pattingre)

In addition to their expression, the activity of ATG proteins, governed by specific post-translational modification, is important for autophagy induction. To this end, we have been interested to several posttranslational modifications such as the BECLIN1/BCL-2 interaction (Pattingre et al, Cell 2005), the regulation of autophagy by MAPKinases (Paillas et al, Autophagy, 2011), and more recently the regulation of ATG protein by acetylation (Sebti et al, PNAS 2014, Sebti et al, Autophagy, 2014). Indeed, we identified the protein BAT3 (also called BAG6) as a major regulator of autophagy through its ability to modulate the intracellular localization of the acetyltransferase EP300 (Figure 1).

PattingreFigEnglish2

Indeed, it is established that the acetylation of ATG5, ATG7, ATG12, LC3 and BECLIN 1 by the acetyltransferase EP300 inhibits autophagy. On the contrary, we demonstrated that P53 acetylation in the nucleus is essential for autophagy. When autophagy is induced by nutrient starvation, BAT3 allows the delocalization of EP300 from the cytoplasm to the nucleus to target P53 thus limiting ATGs protein acetylation in the cytoplasm. In the absence of BAT3 or if BAT3 is mutated on its NLS domain (cytoplasmic localization), EP300 accumulates in the cytoplasm leading to the hyperacetylation of ATGs proteins and constitutive inhibition of autophagy (Sebti et al, PNAS 2014, Sebti et al, Autophagy, 2014).

2- Deregulation of autophagy in colon and prostatic cancer (S. Pattingre, Pr. N. Houédé et Dr. S. Obled)

In colon cancer, in tissue culture and more particularly by studying human tumors, we observed a deregulation in (i) BAT3 intracellular localization, (ii) autophagy (iii) ATGs protein acetylation. The role of BAT3 dependent autophagy in colon and prostatic tumor progression in currently under investigation thanks to a close collaboration with the oncology department of Nimes.

3- Role of autophagy in drug resistance (S. Pattingre et C. Gongora)

The role of BAT3 dependent autophagy in drug resistance in cancer is under investigation thanks to a close collaboration with the oncology department of Nimes (Pr. N. Houédé et Dr. S. Obled). In addition, we recently highlighted the role of P38MAPK in the induction of autophagy during inirinotecan resistance in colon cancer. Our current objective is to identify targets whom phosphorylation by P38MAPK induces autophagy.

References:

Sebti S, Prébois C, Pérez-Gracia E, Bauvy C, Desmots F, Pirot N, Gongora C, Bach AS, Hubberstey AV, Palissot V, Berchem G, Codogno P, Linares LK, Liaudet-Coopman E, Pattingre S. BAT3 modulates p300-dependent acetylation of p53 and ATG7 during autophagy. 2014. PNAS, 111 :4115-20.

Sebti S, Prébois C, Pérez-Gracia E, Bauvy C, Desmots F, Pirot N, Gongora C, Bach AS, Hubberstey AV, Palissot V, Berchem G, Codogno P, Linares LK, Liaudet-Coopman E, Pattingre S. BAG6/BAT3 modulates autophagy by affecting EP300/p300 intracellular localization. 2014. Autophagy. (7):1341-2.

Paillas S, Causse A, Marzi L, de Medina P, Poirot M, Denis V, Vezzio-Vie N, Espert L, Arzouk H, Coquelle A, Martineau P, Del Rio M, Pattingre S, Gongora C. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy. Autophagy (2012) 1;8.

Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B, Codogno P. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. (2009). J Biol Chem. 284:2719-28.

Y. Wei, S. Pattingre, S. Sinha, M. Bassik, and B. Levine. JNK1-Mediated Phosphorylation of Bcl-2 Regulates Starvation-Induced Autophagy. (2008). Molecular Cell. 20:678-688.

Pattingre S., Tassa A., Qu X., Liang H.L., Mishuchima N., Schneider M.D., Parker M. and Levine B. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 122: 927-939.

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