Document Detail


Autophagy is a protective mechanism for human melanoma cells under acidic stress.
MedLine Citation:
PMID:  22761435     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cyclic hypoxia and alterations in oncogenic signaling contribute to switch cancer cell metabolism from oxidative phosphorylation to aerobic glycolysis. A major consequence of up-regulated glycolysis is the increased production of metabolic acids responsible for the presence of acidic areas within solid tumors. Tumor acidosis is an important determinant of tumor progression and tumor pH regulation is being investigated as a therapeutic target. Autophagy is a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, currently considered an important survival mechanism in cancer cells under metabolic stress or subjected to chemotherapy. We investigated the response of human melanoma cells cultured in acidic conditions in terms of survival and autophagy regulation. Melanoma cells exposed to acidic culture conditions (7.0 < pH < 6.2) promptly accumulated LC3+ autophagic vesicles. Immunoblot analysis showed a consistent increase of LC3-II in acidic culture conditions as compared with cells at normal pH. Inhibition of lysosomal acidification by bafilomycin A1 further increased LC3-II accumulation, suggesting an active autophagic flux in cells under acidic stress. Acute exposure to acidic stress induced rapid inhibition of the mammalian target of rapamycin signaling pathway detected by decreased phosphorylation of p70S6K and increased phosphorylation of AMP-activated protein kinase, associated with decreased ATP content and reduced glucose and leucine uptake. Inhibition of autophagy by knockdown of the autophagic gene ATG5 consistently reduced melanoma cell survival in low pH conditions. These observations indicate that induction of autophagy may represent an adaptation mechanism for cancer cells exposed to an acidic environment. Our data strengthen the validity of therapeutic strategies targeting tumor pH regulation and autophagy in progressive malignancies.
Authors:
Maria Lucia Marino; Paola Pellegrini; Giuseppe Di Lernia; Mojgan Djavaheri-Mergny; Slavica Brnjic; Xiaonan Zhang; Maria Hägg; Stig Linder; Stefano Fais; Patrice Codogno; Angelo De Milito
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-09-03     Completed Date:  2012-11-19     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  30664-76     Citation Subset:  IM    
Affiliation:
Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome 00161, Italy.
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / metabolism
Autophagy*
Cell Hypoxia
Cell Line, Tumor
Humans
Hydrogen-Ion Concentration
Lysosomes / metabolism,  pathology
Melanoma / metabolism*,  pathology
Microtubule-Associated Proteins / metabolism
Neoplasm Proteins / metabolism
Phosphorylation
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Stress, Physiological*
TOR Serine-Threonine Kinases / metabolism
Chemical
Reg. No./Substance:
0/ATG5 protein, human; 0/Microtubule-Associated Proteins; 0/Neoplasm Proteins; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 70-kDa
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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