The role of autophagy in tumorigenesis and tumor metastasis remains poorly understood. Here we show that inhibition of autophagy stabilizes the transcription factor Twist1 through Sequestosome-1 (SQSTM1, also known as p62) and thus increases cell proliferation, migration, and epithelial-mesenchymal transition (EMT) in tumor development and metastasis. Inhibition of autophagy or p62 overexpression blocks Twist1 protein degradation in the proteasomes, while p62 inhibition enhances it.
View Article and Find Full Text PDFMitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200.
View Article and Find Full Text PDFBeginning with the earliest studies of autophagy in cancer, there have been indications that autophagy can both promote and inhibit cancer growth and progression; autophagy regulation of organelle homeostasis is similarly complicated. In this review we discuss pro- and antitumor effects of organelle-targeted autophagy and how this contributes to several hallmarks of cancer, such as evading cell death, genomic instability, and altered metabolism. Typically, the removal of damaged or dysfunctional organelles prevents tumor development but can also aid in proliferation or drug resistance in established tumors.
View Article and Find Full Text PDFMany surgical models are used to study kidney and other diseases in mice, yet the effects of the surgical procedure itself on the kidney and other tissues have not been elucidated. In the present study, we found that both sham surgery and unilateral nephrectomy (UNX), which is used as a model of renal compensatory hypertrophy, in mice resulted in increased mammalian target of rapamycin complex 1/2 (mTORC1/2) in the remaining kidney. mTORC1 is known to regulate lysosomal biogenesis and autophagy.
View Article and Find Full Text PDFAutosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by kidney cyst growth often resulting in end-stage renal disease. There is growing attention on understanding the role of impaired autophagy in ADPKD. Trehalose (TRE) has been shown to increase both protein stability and aggregate clearance and induce autophagy in neurodegenerative diseases.
View Article and Find Full Text PDFIn this commentary I discuss a recent paper that describes a new mechanism for how macroautophagy/autophagy regulates the immune response to cancer, and relate it to other recent studies in this area. These recent developments may allow more effective strategies to manipulate autophagy to improve cancer therapy.
View Article and Find Full Text PDFCardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1 and Pkd2 mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1 mouse model of PKD.
View Article and Find Full Text PDFProg Mol Biol Transl Sci
June 2021
The cellular recycling process of macroautophagy, which is the mechanism by which cellular material is delivered to lysosomes via double membraned vesicles called autophagosomes, is intimately connected to programmed cell death pathways, especially apoptosis. In this article, I discuss some underlying mechanisms and their implications for improving cancer therapy and propose that the approaches that have been taken to understand the autophagy-apoptosis connection to enhance cancer drug action can serve as a model for the kinds of information that should be developed to understand how autophagy controls other biological processes as well.
View Article and Find Full Text PDFInt Rev Cell Mol Biol
December 2020
Autophagy, the process of macromolecular degradation through the lysosome, has been extensively studied for the past decade or two. Autophagy can regulate cell death, especially apoptosis, through selective degradation of both positive and negative apoptosis regulators. However, multiple other programmed cell death pathways exist.
View Article and Find Full Text PDFUnlabelled: Macroautophagy/autophagy degrades proteins and organelles to generate macromolecular building blocks. As such, some cancer cells are particularly dependent on autophagy. In a previous paper, we found that even highly autophagy-dependent cancer cells can adapt to circumvent autophagy inhibition.
View Article and Find Full Text PDFIn cancer therapy, a principle goal is to kill cancer cells while minimizing death of normal cells. Traditional cytotoxic therapies and the newer agents that target specific signaling proteins that are critical for cancer cell growth do this by activating a specific type of programmed cell death - apoptosis. However, it has been well established that cancer cells have varying levels of responses to apoptotic stimuli, with some being close to an "apoptotic threshold" and others being further away and that this ultimately determines whether cancer therapy is successful or not.
View Article and Find Full Text PDFAutophagy allows for cellular material to be delivered to lysosomes for degradation resulting in basal or stress-induced turnover of cell components that provide energy and macromolecular precursors. These activities are thought to be particularly important in cancer where both tumor-promoting and tumor-inhibiting functions of autophagy have been described. Autophagy has also been intricately linked to apoptosis and programmed cell death, and understanding these interactions is becoming increasingly important in improving cancer therapy and patient outcomes.
View Article and Find Full Text PDFAutophagy is intricately linked with many intracellular signaling pathways, particularly nutrient-sensing mechanisms and cell death signaling cascades. In cancer, the roles of autophagy are context dependent. Tumor cell-intrinsic effects of autophagy can be both tumor suppressive and tumor promotional.
View Article and Find Full Text PDFAutophagy is cellular recycling process that plays a complex role in cancer. Pre-clinical studies indicating a pro-tumorigenic role of autophagy have led to the launch of dozens of clinical trials combining autophagy inhibition with other standard of care therapies in different tumor types. A recent publication utilized a novel, acute, CRISPR/Cas9 assay to identify cancer cell lines that are exquisitely sensitive to loss of core autophagy genes within the first 7 days.
View Article and Find Full Text PDFWhile autophagy is thought to be an essential process in some cancer cells, it is unknown if or how such cancer cells can circumvent autophagy inhibition. To address this, we developed a CRISPR/Cas9 assay with dynamic live-cell imaging to measure acute effects of knockout (KO) of autophagy genes compared to known essential and non-essential genes. In some cancer cells, autophagy is as essential for cancer cell growth as mRNA transcription or translation or DNA replication.
View Article and Find Full Text PDFSQSTM1/p62 facilitates responses to various cellular stresses and has been implicated in human diseases. This protein functions as a major cytoplasmic signaling hub and has multiple binding partners, including arginylated (Nt-R) proteins that are recognized by the ZZ domain of SQSTM1/p62 (SQSTM1/p62). We have determined the molecular mechanism of Nt-R recognition using a combination of biochemical and NMR approaches and obtained the crystal structure of SQSTM1/p62 in complex with Nt-R.
View Article and Find Full Text PDFAutophagic receptor p62 is a critical mediator of cell detoxification, stress response, and metabolic programs and is commonly deregulated in human diseases. The diverse functions of p62 arise from its ability to interact with a large set of ligands, such as arginylated (Nt-R) substrates. Here, we describe the structural mechanism for selective recognition of Nt-R by the ZZ domain of p62 (p62).
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2018
Molecular alterations that confer phenotypic advantages to tumors can also expose specific therapeutic vulnerabilities. To search for potential treatments that would selectively affect metastatic cells, we examined the sensitivity of lineage-related human bladder cancer cell lines with different lung colonization abilities to chloroquine (CQ) or bafilomycin A, which are inhibitors of lysosome function and autophagy. Both CQ and bafilomycin A were more cytotoxic in vitro to highly metastatic cells compared with their less metastatic counterparts.
View Article and Find Full Text PDFAntiangiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTK) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models.
View Article and Find Full Text PDFThe molecular machinery linking macroautophagy (autophagy hereafter) to apoptosis is still being elucidated. A recent study found that the transcription factor FOXO3/FOXO3A (forkhead box O3), which regulates autophagy, is itself regulated by basal autophagy to determine apoptosis sensitivity. Autophagy inhibition confers cell sensitivity to anti-cancer agents, and this effect is explained by the ability of FOXO3 to transactivate the pro-apoptotic gene BBC3/PUMA.
View Article and Find Full Text PDFRationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms.
Objectives: To test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis.
Macroautophagy (autophagy) is intimately linked with cell death and allows cells to evade apoptosis. This has prompted clinical trials to combine autophagy inhibitors with other drugs with the aim of increasing the likelihood of cancer cells dying. However, the molecular basis for such effects is unknown.
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