Signal-dependent control of autophagy and cell death in colorectal cancer cell: the role of the p38 pathway.
Autophagy is a vacuolar process leading to the degradation of long-lived proteins and cytoplasmic organelles in eukaryotes. This process has an important role in normal and cancer cells during adaptation to changing environmental conditions, cellular and tissue remodeling, and cell death. To date, several signaling cascades have been described to regulate autophagy in a cell type-specific and signal-dependent manner. We found that pharmacological blockade of the p38 pathway in colorectal cancer cells, either by the inhibitor SB202190 or by genetic ablation of p38 alpha kinase, causes cell cycle arrest and autophagic cell death. In these cells, a complex network of intracellular kinase cascades controls autophagy and survival since the effect of p38 alpha blockade is differentially affected by the pharmacological inhibition of MEK1, PI(3)K class I and III, and mTOR or by the differentiation status. Collectively, our results suggest an opportunity for exploiting the pharmacological manipulation of the p38 alpha pathway in the treatment of colorectal cancer. Given the number of drugs, currently available or under development, that target the p38 pathway, it stands to reason that elucidating the molecular mechanisms that link p38 and autophagy might have an impact on the clinical translation of these drugs.
Simone
Cristiano
C
Division of Medical Genetics, Department of Biomedicine in Childhood, University of Bari, Bari, Italy. csimone@temple.edu
D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D005419:Flavonoids / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D002867:Chromones; D005419:Flavonoids; D007093:Imidazoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one