Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity.
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 shown 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 showed 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 Lindane-induced 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 mammalian target of rapamycin and p38 inhibitions. Rather, the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (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.
Corcelle
Elisabeth
E
Institut National de la Santé et de la Recherche Médicale U670, IFR 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 02, France.
Nebout
Marielle
M
Bekri
Soumeya
S
Gauthier
Nils
N
Hofman
Paul
P
Poujeol
Philippe
P
Fénichel
Patrick
P
Mograbi
Baharia
B
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D014617:Vacuoles / Q000187:drug effects / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001556:Hexachlorocyclohexane; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases