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S‐Adenosylmethionine‐mediated apoptosis is potentiated by autophagy inhibition induced by chloroquine in human breast cancer cells
Author(s) -
Cave Donatella Delle,
Desiderio Vincenzo,
Mosca Laura,
Ilisso Concetta P.,
Mele Luigi,
Caraglia Michele,
Cacciapuoti Giovanna,
Porcelli Marina
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26015
Subject(s) - autophagy , apoptosis , cancer cell , poly adp ribose polymerase , pi3k/akt/mtor pathway , chemistry , microbiology and biotechnology , chloroquine , cell growth , biology , cancer research , biochemistry , polymerase , cancer , dna , immunology , genetics , malaria
The naturally occurring sulfonium compound S‐adenosyl‐L‐methionine (AdoMet) is an ubiquitous sulfur‐nucleoside that represents the main methyl donor in numerous methylation reactions. In recent years, it has been shown that AdoMet possesses antiproliferative properties in various cancer cells, but the molecular mechanisms at the basis of the effect induced by AdoMet have been only in part investigated. In the present study, we found that AdoMet strongly inhibited the proliferation of breast cancer cells MCF‐7 by inducing both autophagy and apoptosis. AdoMet consistently enhanced the levels of the autophagy markers beclin‐1 and LC3B‐II, and caused a significant increase of pro‐apoptotic Bax/Bcl‐2 ratio paralleled by poly (ADP ribose) polymerase (PARP) and caspase 9, and 6 cleavage. Notably, AdoMet, already at low doses, raised the percentage of cells in G 2 /M phase of cell cycle by down‐regulating the expression of cell cycle‐regulatory proteins cyclin B and cyclin E with a remarkable increase of p53, p27, and p21. We also evaluated the combination of AdoMet and the autophagy inhibitor chloroquine (CLC) showing that autophagy block is synergistic in inducing both growth inhibition and apoptosis. These effects were paralleled by a strong inhibition of the activity of AKT and of the downstream effector mTOR and by an increased cleavage of caspase‐6 and PARP. These data suggest, for the first time, that autophagy can act as an escape mechanism from the apoptotic activity of AdoMet, and that AdoMet could be used in combination with CLC or its analogs in the treatment of breast cancer.