Content area
Full Text
R E V I E W
Therapeutic targets in cancer cell metabolism and autophagy
Heesun Cheong1, Chao Lu1,2, Tullia Lindsten3 & Craig B Thompson1
The metabolism of cancer cells is reprogrammed both by oncogene signaling and by dysregulation of metabolic enzymes. The resulting altered metabolism supports cellular proliferation and survival but leaves cancer cells dependent on a continuous supply of nutrients. Thus, many metabolic enzymes have become targets for new cancer therapies. Recently, two processesexpression of specific isoforms of metabolic enzymes and autophagyhave been shown to be crucial for the adaptation of tumor cells to changes in nutrient availability. An increasing number of approved and experimental therapeutics target these two processes. A better understanding of the molecular basis of cancer-associated metabolic changes may lead to improved cancer therapies.
npg 2012 Nature America, Inc. All rights reserved.
2012 Nature America, Inc. All rights reserved.
Research over several decades has identified many oncogenes and tumor suppressors that are frequently altered in various tumors. A substantial proportion of these oncogenic abnormalities is associated with growth signaling pathways. Recently, increasing evidence has suggested that growth signaling pathways directly control cell metabolism, growth and proliferation through the regulation of metabolic enzymes. In addition, individual metabolic enzymes have been reported to be mutated or amplified during tumor progression. Understanding how metabolic pathways are altered in tumors and how cancer cells benefit from tumor-specific metabolic changes may contribute to the identification of novel therapeutic targets and the development of more effective cancer therapies.
Although altered metabolism is beneficial to the cancer cell, it can create an increased demand for nutrients to support cell growth and proliferation. At the same time, the inner mass of a tumor may lack adequate nutrients before sufficient angiogenesis has occurred. Metabolic stress is a strong inducer of autophagy, a catabolic process leading to degradation of cellular components through the lysosomal system. Cancer cells use autophagy as a survival strategy to provide essential biomolecules required for cell viability under metabolic stress. In contrast, basal autophagy maintains intracellular organelle homeostasis by eliminating damaged proteins and organelles, which prevents generation of excess reactive oxygen species (ROS) and genome instability. Thus, autophagy is thought to have a key role in the suppression of tumori-genesis. Understanding the context-dependent role of autophagy in...