<i>Atg7</i> cooperates with <i>Pten</i> loss to drive prostate cancer tumor growth

Santanam, Urmila; Banach‐Petrosky, Whitney; Abate‐Shen, Cory; Shen, Michael M.; White, Eileen; DiPaola, Robert S.

doi:10.1101/gad.274134.115

Cited by 107 publications

(88 citation statements)

References 29 publications

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“…In a GEMM for castrate-naïve prostate cancer driven by Pten deficiency, Atg7 deficiency suppresses tumor growth (Santanam et al 2016). Atg7 deficiency increases endoplasmic reticulum stress and reduces tumor cell proliferation.…”

Section: Prostate Cancermentioning

confidence: 99%

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Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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Section: Prostate Cancermentioning

confidence: 99%

“…Atg7 deficiency increases endoplasmic reticulum stress and reduces tumor cell proliferation. Importantly, overall mouse survival is increased by Atg7 deficiency in prostate tumors, and castrate-resistant disease is also suppressed by Atg7 loss (Santanam et al 2016).…”

Section: Prostate Cancermentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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“…However, lung-specific ATG7 deficiency inhibits Kras G12D -driven lung tumor growth and reduction of lung tumor burden with dysfunctional mitochondria and proliferative arrest 5 . ATG7 deficiency produces an autophagy-deficient phenotype and inhibits PTEN (phosphatase and tensin homolog)-deficient prostate tumor progression through management of protein homeostasis under endoplasmic reticulum (ER) stress 6 . Additionally, in our most recent studies, we have shown that ATG7 and its mediated autophagy were much higher in human BC cell lines and N-Butyl-N-(4-hydmoxybutyl)nitrosamine (BBN)-treated UROtsa cells as well as in BBN-induced mouse invasive BCs, which play a promotive role in human BC invasion (J.Z., unpublished data).…”

Section: Introductionmentioning

confidence: 99%

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

Zhu

Yang

Tian

et al. 2017

Molecular Therapy - Nucleic Acids

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Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3′ UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients.

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“…In other GEMMs for cancer, autophagy promotes the growth of Braf V600E -induced lung tumors (Strohecker and White 2014) and Pten-deficient prostate tumors (Santanam et al 2016) and suppresses senescence in melanomas driven by Braf V600E and loss of Pten (Xie et al 2015). Genetic loss of autophagy impairs the progression of Kras-driven premalignant pancreatic intraepithelial neoplasia (PANIN) lesions to invasive cancer (Rosenfeldt et al 2013;Yang et al 2014).…”

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confidence: 99%

Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells

et al. 2016

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Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.

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Atg7 cooperates with Pten loss to drive prostate cancer tumor growth

Cited by 107 publications

References 29 publications

Recent insights into the function of autophagy in cancer

Recent insights into the function of autophagy in cancer

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells

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