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.

Figure 1. Strategies for modulation of autophagy for cancer therapy

(A), Autophagy-mediated survival and regeneration in tumor cells. Stress activates autophagy in tumor cells and in those with apoptotic defects this allows sustained, progressive autophagy and selective cellular self-consumption. This produces small cells that can remain in a dormant state in the presence of stress but when the stress is removed these minimal cells capable of recovery (MCCRs) regenerate and resume cellular proliferation. Autophagy thereby affords cancer cells with the flexibility to tolerate stress, even therapeutic stress, and resume growth when conditions are more favorable. Cancer therapy directed at blocking autophagy-mediated survival with autophagy inhibitors or specific inhibitors targeting the dormancy and recovery process may be extremely valuable. (B), The double-edged sword of autophagy in tumor suppression. Stress activates autophagy, which mitigates damage and promotes senescence that limit tumorigenesis. Autophagy also enables tumor cells to survive metabolic stress, become dormant and regenerate with stress relief that can promote tumorigenesis. In tumors with autophagy defects, damage mitigation is impaired but the surviving, damaged tumor cells, particularly those with genome damage, can promote tumorigenesis. The impaired survival and induction of chronic cell death in tumors can also stimulate inflammation and tumorigenesis. Although autophagy-defective cells may have reduced fitness, these other factors compensate and overall tumorigenesis is stimulated. (C), Autophagy modulation in cancer therapy. Cytotoxic, targeted and radiation therapy amplifies stress and autophagy in addition to the inherent metabolic stress in the tumor microenvironment. Some therapeutics such as angiogenesis inhibitors and 2-deoxyglucose may specifically amplify metabolic stress. Autophagy inhibitors such as HCQ block autophagy, which amplifies damage and cell death while also impairing dormancy and regeneration tilting the balance in favor of tumor regression (blue type). Specific inhibitors of survival such as apoptosis-inducing Bcl-2 inhibitors may work in part by preventing the downstream consequence of productive autophagy. Similarly, dormancy and regeneration inhibitors may be additionally useful anti-cancer therapeutics (blue type). Mechanisms to amplify tumor cell damage by specifically blocking autophagy of proteins or organelles or using proteasome inhibitors in conjunction with autophagy inhibitors should be explored. Alternatively, autophagy stimulators may be useful for cancer prevention by enhancing damage mitigation and senescence (red type).