Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations

Yang, Annan; Rajeshkumar, N. V.; Wang, Xiaoxu; Yabuuchi, Shinichi; Alexander, Brian M.; Chu, Gerald C.; Hoff, Daniel D. Von; Maitra, Anirban; Kimmelman, Alec C.

doi:10.1158/2159-8290.cd-14-0362

Cited by 408 publications

(435 citation statements)

References 33 publications

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“…In vitro studies have shown that the survival of Rasdriven cancer cells requires autophagy and that gaining autophagy results in a marked increase in the survival of malignant cells under conditions of metabolic stress [28] . Inhibiting autophagy by deleting ATG5 prevents the progression of premalignant lesions to cancer in either a p53independent or p53 dependent manner [41,58] . Furthermore, deletion of ATG7 decreases the tumor growth rate and induces nonmalignant tumor formation.…”

Section: Autophagy As a Promoting Factor During Late Stagesmentioning

confidence: 99%

Autophagy in colorectal cancer: An important switch from physiology to pathology

Burada

Nicoli

Ciurea

et al. 2015

WJGO

133

131

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Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of Core tip: This review describes the role of autophagy in cancer, focusing on the involvement of autophagy in colorectal cancer (CRC). Initially, we describe the steps and components of autophagy, and we then further highlight the dual role of autophagy in cancer, where it can potentially act as both a promoter and an inhibitor during the transformation from normal to malignant cell. In particular, we emphasize the major autophagy genes involved in CRC pathogenesis along with autophagymodulating agents and their modes of action in the context of CRC therapy. TOPIC HIGHLIGHT

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Section: Autophagy As a Promoting Factor During Late Stagesmentioning

confidence: 99%

Autophagy in colorectal cancer: An important switch from physiology to pathology

Burada

Nicoli

Ciurea

et al. 2015

WJGO

133

131

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“…However, ablation of ATG5 was reported to either inhibit (13) or promote (16) pancreatitis. In addition, inhibition of autophagy can either accelerate the development of early malignant lesions in mice lacking the transformation-related protein 53 (p53) (19) or cause the death of established pancreatic cancer (20). The latter results gave rise to several ongoing clinical trials (clinicaltrials.gov numbers NCT01494155, NCT01978184, NCT01506973, NCT01128296, and NCT01273805) that intend to evaluate the impact of autophagy inhibitors on human pancreatic cancer.…”

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confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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“…It has been shown that autophagy is elevated and required for de novo tumor growth and that inhibition of autophagy leads to robust tumor regression; 5,6 however, the status of p53 may determine the outcome of autophagy inhibition. 7,8 Despite the complexity of autophagy as a therapeutic target, these studies suggest that disabling the prosurvival autophagy machinery might represent a viable approach to promote cell death and reduce drug resistance in refractory cancers such as pancreatic cancer. 3,9 Because of their potential application as anticancer agents used alone or in combination with other cancer therapeutics, autophagy inhibitors have been actively pursued even though early inhibitors generally lack selectivity or target the lysosomal function.…”

Section: * S Supporting Informationmentioning

confidence: 99%

N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy

Willett

Williams

et al. 2016

ACS Med. Chem. Lett.

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Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure−activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae. Therefore, N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides may represent a new class of autophagy modulators that possesses potent anticancer activity and potentially a novel mechanism of action.KEYWORDS: Autophagy, autophagy modulator, mTOR, pancreatic cancer, anticancer agents M acroautophagy (hereafter referred to as autophagy) is a conserved cellular process through which cytosolic components, such as proteins and organelles, are sequestered, degraded, and recycled. 1 The autophagy machinery requires a number of autophagy-related (Atg) proteins and functional complexes, including the UNC51-like kinase 1 (ULK1) complex, the class III phosphoinositide 3-kinase (PI3K) complex, the Atg12-Atg5-Atg16 ubiquitin-like conjugation system, and the microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine (PE) conjugation system. Among these autophagy components, LC3-II, which is the PE lipidated form of LC3-I, plays a key role. LC3-II is generated after a series of processing by the Atg4-Atg7-Atg3 conjugation machinery. Since it is closely involved in autophagy, the level of LC3-II is commonly used as a marker to monitor autophagy. 2 Autophagy is regulated by a network of complex signaling pathways, where the class I phosphatidylinositol 3-kinase-AKTmammalian target of rapamycin complex 1 (PI3K-AKTmTORC1) pathway is a well-established negative regulator. While a basal level of autophagy is required to maintain cellular homeostasis, it is upregulated in response to lack of nutrients, unfavorable energy status, attenuated growth signaling, virus/ bacteria invasion, and a number of cellular stresses including endoplasmic reticulum stress, oxidative stress, and hypoxia. 3 Activation of autophagy is generally accomplished by inhibiting mTORC1, which in turn increases autophagy by unblocking ULK1. In addition to its role in autophagy, mTORC1 also phosphorylates and regulates substrates including ribosomal protein S6 kinase beta-1 (P70S6K1, hereafter referred to as P70) and 4E-binding protein 1 (4EBP1), and levels of phosphorylated substrates are routinely used to gauge mTORC1 activity.The precise role of autophagy in tumorigenesis and cancer therapy still remains to be defined due to the heterogeneous nature of cancers and the complexity of the autophagy machinery. 4 Studies have shown that autophagy plays different or even opposite roles depending on the cancer type and the stage of tumor progression. Currently, it is ...

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Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations

Cited by 408 publications

References 33 publications

Autophagy in colorectal cancer: An important switch from physiology to pathology

Autophagy in colorectal cancer: An important switch from physiology to pathology

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

N-(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides: Antiproliferative Activity and Effects on mTORC1 and Autophagy

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