The four faces of autophagy: implications for cancer therapy.

It is generally thought that autophagy has two primary and opposing functions in tumor cells in response to stress induced by chemotherapy or radiation. One is the cytoprotective function that can in theory be inhibited for therapeutic advantage by sensitizing the cells to these treatment modalities. The other is the cytotoxic function that is generally not observed with conventional treatment modalities, but that may function to promote tumor cell killing either alone or in association with apoptosis. In this commentary/review, we advance the premise that autophagy is actually populated by at least two additional players. One we have termed the nonprotective form of autophagy, where the cell is apparently carrying out autophagy-mediated degradative functions, but where autophagy inhibition does not lead to perceptible alterations in drug or radiation sensitivity. The other is what we now term the cytostatic form of autophagy in that its activation results in prolonged growth inhibition as well as reduced clonogenic survival (loss of reproductive capacity) but in the absence of actual loss of cell viability through apoptosis or necrosis; however, as is the case with cytototoxic autophagy, inhibition of cytostatic autophagy protects the tumor cell from the agent (drugs or radiation) that promotes the autophagic response. In view of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy for sensitization of malignancies to chemotherapy and radiation, it is critical to recognize that if chemotherapy and/or radiation actually promote autophagy in patient tumors, the autophagy is not of necessity cytoprotective in function.