Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation.
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy.
Puissant
Alexandre
A
INSERM 895, Team 2: Cell Death Differentiation and Cancer, Laboratoire d'Oncohématologie, Centre Hospitalier Universitaire de Nice, Nice, France.
Robert
Guillaume
G
Fenouille
Nina
N
Luciano
Frederic
F
Cassuto
Jill-Patrice
JP
Raynaud
Sophie
S
Auberger
Patrick
P
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D000077185:Resveratrol; D000071456:Sequestosome-1 Protein; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D061945:Caspase Inhibitors; D018942:Macrolides; D010879:Piperazines; D011743:Pyrimidines; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D013267:Stilbenes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C040929:bafilomycin A1; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D020169:Caspases; D025262:Vacuolar Proton-Translocating ATPases; D000077185:Resveratrol