Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III,
The carcinogen Lindane disrupts autophagy at the maturation step by triggering the
MAPK ERK pathway
Elisabeth A. Corcelle1, Marielle Nebout1, Soumeya Bekri2, Nils Gauthier3, Paul
Hofman4, Philippe Poujeol5, Patrick Fénichel1 and Baharia Mograbi1
1INSERM, U670, IFR 50, Faculté de Médecine, Avenue de Valombrose, F-06107 Nice
Cedex 02, France, 2Groupe Appareil Digestif et Environnement (EA3234), Faculté de
Médecine, Bd Gambetta F-76183 Rouen cedex, 3INSERM, U627, IFR50, F-06107 Nice,
4INSERM, E0215/Laboratoire de Pathologie Clinique et Expérimentale, Hôpital
Pasteur, Nice and 5CNRS UMR 6548, Faculté des Sciences, Nice. E-mail :
mograbi@unice.fr
Macroautophagy (hereafter referred to as autophagy) has emerged as a key tumor suppressor
pathway. During this process, the cytosolic constituents are sequestered into autophagosomes,
which subsequently fuse with lysosomes to become autolysosomes where their contents are
finally degraded. Although a reduced autophagy has been demonstrated in human tumors or
in response to oncogenes and carcinogens, the underlying mechanism(s) remain(s) unknown.
Here, we show that widely used carcinogen Lindane promotes vacuolation of Sertoli cells. By
electron and immunofluorescent microscopy analyses, we demonstrated that these structures
are acid autolysosomes, containing cellular debris, and labeled by LC3, Rab7 and LAMP1,
markers of autophagosomes, late endosomes and lysosomes respectively. Such Lindaneinduced
vacuolation results from significant delay in autophagy degradation, in relation with a
decline of the lysosomal activity of Aryl Sulfatase A. At molecular level, we show that this
defect in autolysosomal maturation is independent of mTOR and p38 inhibitions. Rather, the
activation of the mitogen-activated protein kinase (MAPK)/ERK pathway is required for
Lindane to disrupt the autophagic pathway. Most importantly, we provide the first evidence
that sustained activation of ERK pathway is sufficient to commit cell to autophagic
vacuolation. Taken together, these findings strongly support that the aberrant sustained
activation of ERK by the carcinogen Lindane disrupts the maturation of autophagosomes into
functional autolysosomes. Our findings therefore suggest the possibility that high constitutive
ERK activity found in all cancers may provide a malignant advantage by impeding the tumor
suppressive function of autophagy.
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