Autophagy plays an important role in maintaining cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via degradation of aggregated proteins and damaged organelles. Autophagy is associated with the several catabolic and pathological processes, including cancer. Cancer is a multifaceted disorder involving the perturbation of several different pathways that regulate cell proliferation, cell differentiation, and cell survival. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to apoptosis in cancer stem cells. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, rottlerin, from a medicinal plant (Mallotus philippinensis) that induces autophagy in various types of cancer stem cells through the formation of autophagosomes as measured by electron microscopy and GFP-LC3 puncta formation. By computational virtual docking analysis, rottlerin was shown to interact directly with the protein kinase-C delta, beclin-1, and autophagy related proteins. By biochemical assays, rottlerin was shown to increase autophagy induction through the activation of the kinase-AMP-activated protein kinase-mammalian target of rapamycin pathway. In addition, rottlerin treatment causes the induction of apoptosis, which was associated with the suppression of phosphorylated Akt and mTOR, upregulation of phosphorylated kinase-AMP, downregulation of Bcl-2, Bcl-XL, XIAP, and cIAP-1. Rottlerin also proved to be a potent autophagy inducer in cancer stem cells, by knocking down beclin-1, protein kinase-C delta, or Agt7. These results provide a detailed understanding of the mechanism of action of rottlerin, as a novel autophagic inducer by targeting multiple sites to induce autophagy, which leads to the apoptosis in cancer stem cells. Rottlerin has the potential of being developed into an anti-cancer agent by targeting cancer stem cells.
Citation Format: Dhruv Kumar. Rottlerin induced autophagy by targeting multiple sites that leads to the apoptosis in cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 329. doi:10.1158/1538-7445.AM2014-329