Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the ...conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the "serrated pathway", has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (
or
mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.
EMBO J 29 3, 606-618 (2009); published online 10 December 2009Although the essential genes for autophagy (Atg) have been identified, the molecular mechanisms through which Atg proteins control 'self ...eating' in mammalian cells remain elusive. Beclin 1 (Bec1), the mammalian orthologue of yeast Atg6, is part of the class III phosphatidylinositol 3-kinase (PI3K) complex that induces autophagy. The first among an increasing number of Bec1-interacting proteins that has been identified is the anti-apoptotic protein Bcl-2. The dissociation of Bec1 from Bcl-2 is essential for its autophagic activity, and Bcl-2 only inhibits autophagy when it is present in the endoplasmic reticulum (ER). A paper in this issue of the EMBO Journal has identified a novel protein, NAF-1 (nutrient-deprivation autophagy factor-1), that binds Bcl-2 at the ER. NAF-1 is a component of the inositol-1,4,5 trisphosphate (IP3) receptor complex, which contributes to the interaction of Bcl-2 with Bec1 and is required for Bcl-2 to functionally antagonize Bec1-mediated autophagy. This work provides mechanistic insights into how autophagy- and apoptosis-regulatory molecules crosstalk at the ER.
Cancers are often affected by derangements in mitochondrial (mt) function, as well as mtDNA mutations. In this issue, Tan et al. (2015) demonstrate that only mtDNA-depleted cancer cells capable of ...recovering mtDNA from the host form metastasizing cancers in vivo, revealing an essential requirement for oxidative phosphorylation in tumor progression.
Cancers are often affected by derangements in mitochondrial (mt) function, as well as mtDNA mutations. In this issue, Tan et al. (2015) demonstrate that only mtDNA-depleted cancer cells capable of recovering mtDNA from the host form metastasizing cancers in vivo, revealing an essential requirement for oxidative phosphorylation in tumor progression.
In a screen designed to identify novel inducers of autophagy, we discovered that STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic inhibition of STAT3 stimulated autophagy ...in vitro and in vivo, while overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2α kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2α hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate. STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2α phosphorylation, which facilitates autophagy induction. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners.
► Inhibition of STAT3 stimulates autophagic flux, in vitro and in vivo ► In baseline conditions, STAT3 interacts with the eIF2α kinase PKR ► In response to autophagic triggers, the STAT3-PKR interaction is disrupted ► By binding to PKR, STAT3 controls autophagy in a transcription-independent fashion
Organelle-Specific Initiation of Autophagy Sica, Valentina; Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel ...
Molecular cell,
08/2015, Letnik:
59, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Autophagy constitutes a prominent mechanism through which eukaryotic cells preserve homeostasis in baseline conditions and in response to perturbations of the intracellular or extracellular ...microenvironment. Autophagic responses can be relatively non-selective or target a specific subcellular compartment. At least in part, this depends on the balance between the availability of autophagic substrates (“offer”) and the cellular need of autophagic products or functions for adaptation (“demand”). Irrespective of cargo specificity, adaptive autophagy relies on a panel of sensors that detect potentially dangerous cues and convert them into signals that are ultimately relayed to the autophagic machinery. Here, we summarize the molecular systems through which specific subcellular compartments—including the nucleus, mitochondria, plasma membrane, reticular apparatus, and cytosol—convert homeostatic perturbations into an increased offer of autophagic substrates or an accrued cellular demand for autophagic products or functions.
Sica, Galluzzi, et al. discuss the molecular systems through which perturbations of homeostasis are detected at specific subcellular compartments and converted into signals that drive non-selective or highly targeted autophagic responses.
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM ...hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.
•Short-term fasting improves anticancer chemotherapy•Treatment with caloric restriction mimetics (CRMs) inhibits tumor growth in vivo•CRMs trigger an autophagy-dependent anticancer immune response•CRMs deplete regulatory T Cells from tumor bed
Pietrocola et al. show that short-term fasting or autophagy-inducing caloric restriction mimetics, such as hydroxycitrate and spermidine, improves the antitumor efficacy of chemotherapy in vivo. The effect is specific for autophagy-competent tumors and depends on regulatory T cell depletion from the tumor bed.
Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many ...oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
Autophagy has been described to have tumor‐suppressive as well as tumor‐promoting functions. This review discusses how stage and context alters the role for autophagy in cancer, and argues for further research prior to targeting autophagy in cancer therapy.
Abstract Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as ...a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-κB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors.
The response to neoadjuvant chemoradiation (nCRT) is a critical step in the management of locally advanced rectal cancer (LARC) patients. Only a minority of LARC patients responds completely to ...neoadjuvant treatments, thus avoiding invasive radical surgical resection. Moreover, toxic side effects can adversely affect patients' survival. The difficulty in separating in advances responder from non-responder patients affected by LARC highlights the need for valid biomarkers that guide clinical decision-making. In this context, microRNAs (miRNAs) seem to be promising candidates for predicting LARC prognosis and/or therapy response, particularly due to their stability, facile detection, and disease-specific expression in human tissues, blood, serum, or urine. Although a considerable number of studies involving potential miRNA predictors to nCRT have been conducted over the years, to date, the identification of the perfect miRNA signatures or single miRNA, as well as their use in the clinical practice, is still representing a challenge for the management of LARC patients. In this review, we will first introduce LARC and its difficult management. Then, we will trace the scientific history and the key obstacles for the identification of specific miRNAs that predict responsiveness to nCRT. There is a high potential to identify non-invasive biomarkers that circulate in the human bloodstream and that might indicate the LARC patients who benefit from the watch-and-wait approach. For this, we will critically evaluate recent advances dealing with cell-free nucleic acids including miRNAs and circulating tumor cells as prognostic or predictive biomarkers.
Cellular metabolism and diseases Maiuri, Maria Chiara; Maffia, Pasquale
British journal of pharmacology,
20/May , Letnik:
178, Številka:
10
Journal Article
Recenzirano
Odprti dostop
LINKED ARTICLES
This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit ...http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc
PDF
