Cancer therapy beyond apoptosis: autophagy and anoikis as mechanisms of cell death.

ABSTRACT

Apoptosis has long been recognized as a critical mechanism of programmed cell death that is preserved among all eukaryotes and is involved in a variety of disease processes. Malignant transformation of cells is associated with a constellation of pro-survival mutations rendering them resistant to apoptosis. Traditional cancer therapy evokes cell death by inducing apoptosis; however, the apoptotic resistance inherent in cancer cells has been a significant barrier to effective chemotherapy. More recently, other mechanisms of cell death have emerged as potential novel mechanisms for cancer therapies to induce cell death, either in addition to, or instead of, apoptosis-induced cytotoxic treatment. Autophagy is a process that occurs in all cells, but is induced in many types of cancer. Autophagy functions as both a cell survival and a cell death mechanism depending on the context and the stimuli, which are likely exploitable for cancer therapy. Anoikis is also a physiologic process in normal cells used to maintain homeostasis, in which cell death is induced in response to loss of extracellular membrane (ECM) attachment. Cancer cells are notoriously resistant to anoikis, enabling metastasis and new tumor growth beyond their original environment. Interestingly, autophagy may actually by a major contributor to anoikis resistance in cancer. As these two processes are elucidated in more detail, there is great potential for novel targets that affect cancer cell death, in addition to the current cytotoxic agents.