1. Autophagy in cancer biology and therapy Noor GAMMOH;Simon WILKINSON ;
Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, United Kingdom, EH4 2XR ;
Fig.2 Potential manipulation of autophagy during anti-cancer therapy. Highlighted using red lines are potential molecules that can be targeted to inhibit autophagy meanwhile in green line are potential ways to activate autophagy. 1 Autophagy can be activated using anti-cancer agents e.g. Etoposide & Cisplatin, mTOR inhibitors e.g. Rapamycin & CCI-779, small peptides and leucine starvation. 2 Inhibiting ULK1 kinase activity is of interest to disrupt autophagy. However, ULK complex proteins have non-autophagic functions and autophagy can take place in their absence. 3 The class III PI3K, Vps34, is currently being targeted to inhibit autophagy using inhibitors such as 3-MA and wortmannin. Vps34 is also involved in endosomal trafficking and its inhibition can disrupt autophagy as well as multiple cellular functions. 4 Targeting core autophagy machinery may provide some specificity. Individual members of the ATG5 complex have autophagy-independent activities involving DNA damage response, apoptosis, immune response and mitochondrial function. Disrupting the complex formation e.g. by inhibiting ATG5-ATG12 conjugation may specifically abrogate autophagy. E1- and E2-like enzymes have non-autophagy functions; however targeting their enzymatic activities may lead to specific inhibition of autophagy. 5 Potential disruption of autophagosome-lysosome fusion may be specific to autophagy. The molecular players involved are not yet identified. 6 Pharmacological inhibition of lysosome function e.g. using CQ or Bafilomycin A1 may affect carcinogenesis independently of autophagy. Furthermore, the disruption of autophagy at either early stages involving autophagosome formation or later events that abrogate autophagic degradation can lead to differential consequences during anti-cancer therapy as discussed in the text.
Frontiers in Biology,2014,9(1), Doi: /s