Autophagy Opposes p53-Mediated Tumor Barrier to Facilitate Tumorigenesis in a Model of <i>PALB2</i>-Associated Hereditary Breast Cancer

Huo, Yanying; Cai, Hong; Teplova, Irina; Bowman-Colin, Christian; Chen, Guanghua; Price, Sandy M.; Barnard, Nicola; Ganesan, Shridar; Karantza, Vassiliki; White, Eileen; Xia, Bing

doi:10.1158/2159-8290.cd-13-0011

Cited by 116 publications

(123 citation statements)

References 48 publications

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“…41,42 In contrast, a recent study using palb2 knockout mice suggests that autophagy promotes mammary tumor growth by suppressing TP53/TRP53/p53 (note that the mouse nomenclature is TRP53, but we use TP53 hereafter to refer to both the human and mouse genes/proteins for simplicity) activation induced by DNA damage. 43 Although these 2 roles appear contradictory on the surface, evidence is emerging to suggest that the impact of autophagy in a given tumor will be context-specific, likely influenced by the genotype or phenotype of the tumor as well as the stage of tumorigenesis. That said, in most established tumor models studied to date autophagy is cytoprotective and confers resistance to cancer treatments, including chemotherapy and radiation.…”

Section: Discussionmentioning

confidence: 99%

A role for ABCG2 beyond drug transport: Regulation of autophagy

et al. 2016

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The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug-resistant phenotype. However, studies over the past several years suggest that the ABC transporters may play additional role(s) in cell survival in the face of stress inducers that are not ABCG2 substrates (i.e., nutrient deprivation, ionizing radiation, rapamycin). The mechanism by which this occurs is largely unknown. In the present study, using several cancer cell lines and their ABCG2-overexpressing sublines, we show that cells overexpressing ABCG2 were more resistant to these stressors. This resistance was associated with an elevated level of autophagy flux, as measured by a higher rate of SQSTM1/p62 degradation and greater accumulation of LC3-II when compared to parental cells. Knockdown of ABCG2 reduced autophagic activity in resistant cells to a level similar to that observed in parental cells, confirming that the enhanced autophagy was ABCG2-dependent. Moreover, using cell viability, apoptosis, and clonogenic assays, we demonstrated that the ABCG2-expressing cells were more resistant to amino acid starvation and radiation-induced cell death. Importantly, knockdown of the critical autophagy factors ATG5 and ATG7 greatly reduced cell survival, verifying that enhanced autophagy was critical for this effect. Taken together, these data indicate that autophagy induced by various stressors is enhanced/accelerated in the presence of ABCG2, resulting in delayed cell death and enhanced cell survival. This defines a new role for this transporter, one with potential clinical significance.

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Section: Discussionmentioning

confidence: 99%

A role for ABCG2 beyond drug transport: Regulation of autophagy

et al. 2016

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“…Moreover, hereditary breast and ovarian cancer arises from missense mutations in BRCA1 with subsequent loss of the wild-type allele that may or may not include deletion of BECN1 (19). In genetically engineered mouse models (GEMMs) for hereditary breast cancer, allelic loss of Becn1 promotes p53 activation and reduces tumorigenesis, which is the opposite result expected if Becn1 is acting as a tumor suppressor (20). Note that large-scale genomic analysis of human cancers to date has failed to identify recurrent mutations in BECN1 or other essential autophagy genes (21,22).…”

Section: Autophagy As a Tumor Promotermentioning

confidence: 99%

The role for autophagy in cancer

White¹

2015

J. Clin. Invest.

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1,135

965

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Autophagy is a tissue-specific regulator of homeostasis and survivalAutophagy captures and degrades intracellular components such as proteins and organelles to sustain metabolism and homeostasis. Low levels of basal autophagy prevent the gradual accumulation of damaged proteins and organelles in tissues that is toxic over time; thus, autophagy plays an important role in protein and organelle quality control (1). Identification of the autophagy substrates that are deregulated in autophagy-deficient cells and tissues is important to understand the biological role and tissue specificity of autophagy. Determination of the global impact of autophagy on the cellular proteome would be a significant advance, as we are only beginning to understand the broad scope of autophagy substrates and the functional consequence of deregulating their degradation and recycling.Some tissues such as liver, brain, and muscle are particularly dependent on autophagy to prevent the buildup of damaged mitochondria and protein aggregates containing the autophagy substrate p62/SQSTM1 (p62) and ubiquitin (1). Accumulation of defective mitochondria that results from impaired autophagy can perturb metabolism and generate oxidative stress (2). Autophagy also mitigates ER stress, and autophagy defects can produce accumulation of chaperone proteins that increase the unfolded protein burden (3, 4). Select protein elimination by autophagy is also important for homeostasis. The toxicity of autophagy defects in liver is partly ameliorated by deficiency in the autophagy substrate p62, but this is not the case for the brain (5, 6). The recent revelation that autophagy is important for recycling iron complexed with ferritin through ferritinophagy may be critical for iron homeostasis in many tissues, potentially including brain (7).The accumulation of, or imbalance in, levels of some cellular components caused by autophagy defects may be indirect. For example, lipid accumulation in autophagy-deficient liver and some lung tumors can arise from defects in the autophagy of lipid droplets through lipophagy (8) or indirectly from defects in mitochondrial fatty acid oxidation (FAO) that repress lipid catabolism (9). These findings collectively demonstrate the broad effects of autophagy on cellular homeostasis at the level of substrate removal, maintenance of organelle function, and detoxification. Thus, autophagy dependence is tissue specific, not only for the general requirement for the level of autophagic activity, but also for the nature of the substrates that require autophagy-mediated elimination or recycling.Acute autophagy induction is critical for yeast and normal mammalian cells and mammals to survive starvation, which is attributed to the recycling of intracellular components into metabolic pathways (2). Autophagy thereby functions to promote metabolic homeostasis and survival that is essential during nutrient deprivation. While it is generally appreciated that autophagy-mediated degradation of intracellular proteins and organelles provides metabolic s...

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“…For example, FIP200 deletion significantly reduced proliferation and suppressed mammary tumor initiation and progression in a mouse model of breast cancer driven by the PyMT oncogene [59] . In a Palb2 knockout mouse model, he terozygous deletion of the autophagy gene BECN1 reduced Palb2associated mammary tumorigenesis in a p53dependent manner, indicating that in the presence of DNA damage and oxidative stress, autophagy can support tumor development by suppressing p53 [60] . Autophagy can improve the resistance of cancer cells to detachment from the basal membrane, resulting in transformed cells that are less sensitive to therapy induced cell death.…”

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

138

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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Autophagy Opposes p53-Mediated Tumor Barrier to Facilitate Tumorigenesis in a Model of PALB2-Associated Hereditary Breast Cancer

Cited by 116 publications

References 48 publications

A role for ABCG2 beyond drug transport: Regulation of autophagy

A role for ABCG2 beyond drug transport: Regulation of autophagy

The role for autophagy in cancer

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

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