Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death.
The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy.
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
A
A
Kondratskyi
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
M
M
Yassine
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
C
C
Slomianny
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
K
K
Kondratska
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
D
D
Gordienko
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
E
E
Dewailly
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
V
V
Lehen'kyi
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
R
R
Skryma
Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
N
N
Prevarskaya
D001343:Autophagy / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008954:Models, Biological; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D001381:Azepines; C056218:ML 9; C546842:MTOR protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002118:Calcium