Principles and Current Strategies for Targeting Autophagy for Cancer Treatment

Amaravadi, Ravi K.; Lippincott‐Schwartz, Jennifer; Yin, Xiao Ming; Weiss, William A.; Takebe, Naoko; Timmer, William C.; DiPaola, Robert S.; Lotze, Michael T.; White, Eileen

doi:10.1158/1078-0432.ccr-10-2634

Cited by 797 publications

(781 citation statements)

References 110 publications

(126 reference statements)

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“…Known autophagy inhibitors that are FDA approved for alternative indications are now being studied in clinical trials, primarily as cancer therapeutics. 53,54 Use of these agents may prove a rapid means to translate our findings to novel treatments of mucin secretion and chronic lung disease.…”

Section: Discussionmentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagyrelated 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

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Section: Discussionmentioning

confidence: 99%

IL13 activates autophagy to regulate secretion in airway epithelial cells

et al. 2016

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“…38 Combination chemotherapy is widely used to treat cancer and is more effective than single chemotherapy because of resistance to single chemical treatments. 39 Several lines of evidence implicates a paradoxical role of autophagy following anticancer treatments.…”

Section: Discussionmentioning

confidence: 99%

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

Huang

Qiu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: BAFA1, bafilomycin A1; CPT, Camptothecin; miRNA, microRNA; LC3, microtubule-associated protein 1 light chain 3; mTOR, mechanistic target of rapamycin; Rictor, Rptor independent companion of mTOR complex 2; MUT, mutated; UTR, untranslated region; NC, negative control.It has been reported that persistent or excessive autophagy promotes cancer cell death during chemotherapy, either by enhancing the induction of apoptosis or mediating autophagic cell death. Here, we show that miR-15a and miR-16 are potent inducers of autophagy. Rictor, a component of mTORC2 complex, is directly targeted by miR-15a/16. Overexpression of miR-15a/16 or depletion of endogenous Rictor attenuates the phosphorylation of mTORC1 and p70S6K, inhibits cell proliferation and G1/S cell cycle transition in human cervical carcinoma HeLa cells. Moreover, miR15a/16 dramatically enhances anticancer drug camptothecin (CPT)-induced autophagy and apoptotic cell death in HeLa cells. Collectively, these data demonstrate that miR-15a/16 induced autophagy contribute partly to their inhibition of cell proliferation and enhanced chemotherapeutic efficacy of CPT.

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“…Cytotoxic drugs induce autophagy, most likely by causing damage to DNA, cellular proteins, and organelles. 1 Many such categories of cytotoxic drugs induced cellular damages that are reversible, 1 and autophagy is critical in this damage-control microenvironment. Ample evidence supports the hypothesis that the cells toggle between the 2 responses in a mutually exclusive manner.…”

Section: Introductionmentioning

confidence: 99%