Journal
CELL DEATH & DISEASE
Volume 5, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/cddis.2014.156
Keywords
ML-9; autophagy; cell death; lysosomotropic agents; calcium
Categories
Funding
- INSERM
- Ligue Nationale Contre le Cancer
- Ministere de l'Education Nationale
- Region Nord/Pas-de-Calais
- FRM (Fondation de Recherche Medicale)
- Erasmus Mundus
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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.
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