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The β-carboline alkaloids are plant substances that exhibit a wide spectrumof neuropharmacological, psychopharma-cological and antitumor effects. In thepresent study, we found that harmol, a β-carboline alkaloid, induced autophagyand suppression of survivin expression, and subsequently induced apoptotic celldeath in U251MG human glioma cells. Autophagy was induced within 12 h by treatmentwith harmol. When treated for over 36 h, however, apoptotic cell death was induced.Harmol treatment also reduced survivin protein expression. Small interfering RNA(siRNA)-mediated knockdown of survivin enhanced the harmol-induced apoptosis.Knockdown of survivin by siRNA also induced autophagy. Therefore, harmol-inducedapoptosis is a result of the reduction in survivin protein expression. Treatmentwith 3-methyladenine (3-MA) in the presence of harmol did not affect the expressionof survivin and diminished harmol-induced cell death. Treatment with chloroquinein the presence of harmol did not suppress the reduction of survivin expressionand increased harmol-induced cell death. From these results, harmol-induced reductionof survivin expression was closely related to autophagy. It is assumed that whenisolation membrane formation is inhibited by treatment with 3-MA, reduction ofsurvivin protein expression and apoptotic cell death were not induced. However,when isolation membrane formation is started and an autophagosome is formed, survivinexpression is suppressed and apoptosis is executed. Harmol treatment reduced phosphorylationof Akt, mammalian target of rapamycin (mTOR) and its downstream targets p70-ribosomalprotein S6 kinase and 4E-binding protein 1, resulting in induction of autophagy.Conversely, activation of the Akt/mTOR pathway inhibited harmol-induced autophagyand cell death. These findings indicate that harmol-induced autophagy involvesthe Akt/mTOR pathway. Taken together, autophagy induced by harmol representeda pro-apoptotic mechanism, and harmol suppressed the expression of survivin andsubsequently induced apoptosis.

Harmol induces autophagy and subsequent apoptosis in U251MG human glioma cells through the downregulation of survivin