Role of autophagy in suppression of inflammation and cancer

White, Eileen; Karp, Cristina M.; Strohecker, Anne M.; Guo, Yanxiang; Mathew, Robin

doi:10.1016/j.ceb.2009.12.008

Cited by 289 publications

(236 citation statements)

References 48 publications

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“…Autophagy is a crucial component of the cellular stress adaptation response (White et al, 2010), and its pathways have been demonstrated to play a key role in fine-tuning inflammatory responses in keratinocytes (Fésüs et al, 2011). Mitochondria play a central role in the initiation of inflammasomes and other inflammatory pathways (Green et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

Sun

Zheng

et al. 2014

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tThe human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro-and antiinflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1␣ and tumor necrosis factor-␣ (TNF-␣), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions.

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Section: Introductionmentioning

confidence: 99%

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

Sun

Zheng

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…8 Autophagy has emerged as a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles, and buffering metabolic stress induced under starvation conditions by recycling intracellular constituents. 9 Autophagosomes engulfing organelles then fuse with lysosomes and mature into autolysosomes.…”

mentioning

confidence: 99%

“…Although previous findings strongly suggest that autophagy contributes to sustainable cell survival, antitumorigenic roles of autophagy have been also mentioned. 8 Autophagy has roles in protecting cells against shortage of nutrients. Cells supply amino acids from self-digested organelles as an alternative energy source for their survival.…”

mentioning

confidence: 99%

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Hou

Dong

Tan

et al. 2011

Laboratory Investigation

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Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity. Intrahepatic cholangiocellular carcinoma (ICC) is a malignant neoplasm originating from epithelium of the biliary tree with high mortality. 1 ICC accounts for 5-30% of all primary liver malignancies, and its incidence has been increasing over the last several decades. 2 The mortality from intrahepatic cholangiocarcinoma is very high, with the 5-year survival rates being o15-20% in most series. 3,4 However, the exact molecular mechanisms of biliary epithelium malignant transformation are not well understood. Despite improved diagnostic and operative techniques, the prognosis of ICC remains poor. 5 Indeed, ICC is a type of cancer highly resistant to conventional antineoplastic medicines, 4 which is partially attributed to the property of insensitivity to cell death induced by cytotoxic agents. It is well known that the avoidance of apoptosis is one of the hallmarks of cancer cells, 6 and that failure to induce apoptosis by anticancer treatments contributes to chemotherapeutic failure and tumor progression. Although autophagy, an alternative caspase-independent cell death program, 7 is thought to be used for cancer treatment, its underlying molecular mechanism is still controversial in antineoplastic therapy and also in tumor progression.Autophagy is a conserved catabolic process by which cells themselves digest their organelles. 8 Autophagy has emerged as a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles, and buffering metabolic stress induced under starvation conditions by recycling intracellular constituents. 9 Autophagosomes engulfing organelles then fuse with lysosomes and mature into autolysosomes. Autophagic processes have been well characterized in yeast, and 430 autophagy-related genes that encode the proteins executing autophagy have been identified in the field of yeast genetics. 6,7 The amino acids and fatty acids generated by autophagic degr...

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“…With the "MetaDE" package of R project, we merged the three expression profiles and screened the differentially- pathway-gene information, we constructed an ARP [13] complex network. Four topological properties (degree, average shortest path length, closeness centrality, and clustering coeffi cient of the ARP network) were analyzed by the "network analyzer" plugin in Cytoscape software (www.…”

Section: Gene Expression Signifi Cance Analysismentioning

confidence: 99%

“…Cerebral ischemia-induced microglial autophagy contributes to ischemic neuronal inflammation and injury. Autophagy is a process for the intracellular bulk degradation of cellular constituents that has multiple effects on immunity [12][13][14] . Blocking autophagy in epithelial cells enhances host cell death and finally leads to tissue destruction and infl ammation [15] .…”

Section: Introductionmentioning

confidence: 99%

Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression

et al. 2015

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Autophagy plays a vital role in cerebral ischemia and may be a potential target for developing novel therapy for stroke. In this study, we constructed an autophagy-related pathway network by analyzing the genes related to autophagy and ischemic stroke, and the risk genes were screened. Two autophagy-related modules were signifi cantly up-regulated and clustered to influence cerebral ischemia. Besides, three key modular genes (NFKB1, RELA, and STAT3) were revealed. With 5-fold cross validation, the ROC curves of NFKB1, RELA, and STAT3 were 0.8256, 0.8462, and 0.8923. They formed a complex module and competitively mediated the activation of autophagy in cerebral ischemia. In conclusion, a module containing NFKB1, RELA, and STAT3 mediates autophagy, serving as a potential biomarker for the diagnosis and therapy of ischemic stroke.

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Role of autophagy in suppression of inflammation and cancer

Cited by 289 publications

References 48 publications

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Identification of autophagy signaling network that contributes to stroke in the ischemic rodent brain via gene expression

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