Pro-Death or Pro-Survival: Contrasting Paradigms on Nanomaterial-Induced Autophagy and Exploitations for Cancer Therapy.

Autophagy is a critical lysosome-mediated cellular degradation process for the clearance of damaged organelles, obsolete proteins, and invading pathogens and plays important roles in the pathogenesis and treatment of human diseases including cancer. While not a cell death process per se, autophagy is nevertheless intimately linked to a cell's live/die decision. Basal autophagy, operating constitutively at low levels in essentially every mammalian cell, is vital for maintaining cellular homeostasis and promotes cell survival. On the other hand, elevated level of autophagy is frequently observed in cells responding to a physical, chemical, or biological stress. This "induced" autophagy, a hallmark under a variety of pathological and pathophysiological conditions, may be either pro-death or pro-survival, two contrasting paradigms for cell fate determination. Research in our laboratory and other groups around the world over the last 15 years has revealed nanomaterials as a unique class of autophagy inducers, with the capability of elevating the cellular autophagy to extremely high levels. In this Account we focus on the contrasting cell fate decision impacted by nanomaterial-induced autophagy. First, we give a brief introduction to nanomaterial-induced autophagy and summarize our current understanding on how it affects a cell's live/die decision. Autophagy induced by nanomaterials, in most cases, promotes cell death, but a significant number of nanomaterials are also able to elicit pro-survival autophagy. Although not a common feature, some nanomaterials may induce pro-death autophagy in one cell type while eliciting pro-survival autophagy in a different cell type. The ability to control the level of the induced autophagy, and furthermore its pro-death/pro-survival nature, is critically important for nanomedicine. Second, we discuss several possible mechanistic insights on the pro-death/pro-survival decision for nanomaterial-induced autophagy. "Disrupted" autophagic processes, with a "block" or perhaps "diversion" at the various stages, may be a characteristic hallmark for nanomaterial-induced autophagy, rendering it intrinsically pro-death in nature. On the other hand, autophagy-mediated upregulation and activation of pro-survival factors or signaling pathways, overriding the intrinsic pro-death nature, may be a common mechanism for nanomaterial-induced pro-survival autophagy. In addition, cargo degradation and reactive oxygen species may also play important roles in the pro-death/pro-survival decision impacted by nanomaterial-induced autophagy. Finally, we focus on the situation where nanomaterials induce autophagy in cancer cells and summarize the different strategies in exploiting the pro-death or pro-survival nature of nanomaterial-induced autophagy to enhance the various modalities of cancer therapy, including direct cancer cell killing, chemotherapy and radiotherapy, photothermal therapy, and integrated diagnosis and therapy. While the details vary, the basic principle is simple and straightforward. If the induced autophagy is pro-death, maximize it. Otherwise, inhibit it. Effective exploitation of nanomaterial-induced autophagy has the potential to become a new weapon in our ever-increasing arsenal to fight cancer, particularly difficult-to-treat and drug-resistant cancer.