The Double-Edged Sword of Autophagy Modulation in Cancer

Abstract

Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive, in which it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage, and sustains viability under adverse conditions. Autophagy is a tumor-suppression mechanism, yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention. (Clin Cancer Res 2009;15(17):5308-16) Autophagy Is a Lysosomal Degradation Pathway for Intracellular DigestionStress stimuli activate cellular pathways for adaptation that are crucial for cells to either tolerate adverse conditions or to trigger cell suicide mechanisms, such as apoptosis to eliminate damaged and potentially dangerous cells (1). Metabolic stress, including starvation, increases the cellular requirement for energy production and damage mitigation, and catabolic cellular self-digestion by autophagy plays a critical role in both instances. Stress activates autophagy, in which double membrane vesicles form and engulf proteins, cytoplasm, protein aggregates, and organelles that are then delivered to lysosomes where they are degraded (2). Autophagy serves to maintain cellular metabolism through recycling of cellular components when the availability of external nutrient sources is limited. Autophagydeficient mice have tissues with low ATP levels and fail to survive the neonatal starvation period, providing a clear example of autophagy-mediated management of energy homeostasis (3). Stress, particularly resulting from oxidative damage due to aging or hypoxic conditions, damages proteins and organelles that require autophagy for elimination. Mice with autophagy defects accumulate cells with polyubiquitinated p62 (sequestosome1)-containing protein aggregates and damaged mitochondria and show elevated oxidative stress and cell death (4-8). Thus, autophagy is important for the degradative turnover of damaged proteins and organelles during stress, the failure of which is toxic to cells and tissues and can be pro-inflammatory. Peptides generated from proteins degraded by autophagy can also be used for antigen presentation to T cells for regulation of immunity and host defense (9). The importance of autophagy as a homeostatic and survival-promoting mechanism is underscored by the association of autophagy defects in t...

Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia

“…[56][57][58][59][60][61][62] The downstream inhibitors of autophagy chloroquine and hydroxychloroquine suppress tumor growth in a laboratory mouse model 63 and have been used in clinical trials of human patients. 56,[59][60][61][62]64 In a clinical trial, the addition of chloroquine has significantly improved median survival of patients with glioblastoma receiving conventional chemotherapy and radiotherapy. 65 However, other studies suggest that chloroquine or hydroxychloroquine is not effective in some types of cancer cells.…”

“…ACTB was used as a loading control. many anticancer agents can induce autophagy, 17,56,62 it is critical to understand the effects of autophagy on cell survival and death when combining anticancer agents with an autophagy inhibitor. It has been demonstrated that an autophagy inhibitor can sensitize cancer cells to the treatment with some anticancer agents such as histone deacetylase (HDAC) inhibitors by taking advantage of the cell survival role of autophagy.…”

Apoptosis promotes early tumorigenesis

“…Autophagy, or programmed cell survival, shares several common stimuli and signaling pathways with those of apoptosis (Maiuri et al, 2007). Autophagy is a tumorsuppression mechanism, yet it enables tumor-cell survival in settings of enhanced stress (Kondo et al, 2005;Mathew et al, 2007;White and DiPaola, 2009). Moreover, autophagy can degrade active caspase-8 within tumor cells (Hou et al, 2010).…”

MicroRNA

“…There is mounting evidence to link autophagy and cancer, 51,52 and the role of autophagy in cancer progression is still unclear. Several reports demonstrated that activation of autophagy may suppress tumor development and lead to cell death.…”

“…[59][60][61] Contrary to this, other studies have shown an anticancer role by enhancing autophagy. 47,52,62,63 Table 1 provides a list of miRNAs reported with therapeutic potential for treating cancer. It seems clear that the unique oncogenes/pathways involved in autophagy, the specific tumor type and tumor environment and the disease context are some of the key factors to be considered for developing autophagy-mediated anticancer strategies.…”