The Switch between Protective and Nonprotective Autophagy; Implications for Autophagy Inhibition as a Therapeutic Strategy in Cancer

Autophagy, a process of cellular self-degradation and cell survival whereby the cell generates energy and metabolic intermediates under conditions of stress (i.e., nutrient deprivation), is also commonly induced in tumor cells in response to chemotherapy and radiation. While chemotherapy-induced autophagy and radiation-induced autophagy are generally considered to have cytoprotective functions, thereby reducing tumor cell sensitivity (and potentially conferring resistance) to various treatment modalities, autophagy can also be nonprotective; furthermore, the nature of the autophagy can be altered via the "autophagic switch" depending on such factors as the p53 status of the tumor cells. Defective or compromised autophagy has also been associated with neurodegenerative diseases, raising concerns as to the impact of autophagy inhibition on normal tissue function. Furthermore, the impact of autophagy inhibition on the immune system response to therapy as well as the influence of autophagy inhibition in combination with chemotherapy or radiation on critical tissue sites such as the bone marrow remain uncertain. These are factors requiring serious consideration within the context of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy in cancer.