Cell Stress最新文献

Tryptophan is one of the eight essential amino acids that must be obtained from the diet. Interestingly, tryptophan is the least abundant amino acid in most proteins, a large portion of cellular tryptophan is converted into metabolites of the serotonin and kynurenine pathways. In a recent study, (Venkateswaran, Lafita-Navarro et al., 2019, Genes Dev), we discovered that colon cancer cells display greater uptake and processing of tryptophan than normal colonic cells and tissues. This process is mediated by the oncogenic transcription factor MYC that promotes the expression of the tryptophan importers SLC1A5 and SLC7A5 and the tryptophan metabolizing enzyme AFMID. The metabolism of tryptophan in colon cancer cells generates kynurenine, a biologically active metabolite necessary to maintain continuous cell proliferation. Our results indicate that kynurenine functions as an oncometabolite, at least in part, by activating the transcription factor AHR, which then regulates growth promoting genes in cancer cells. We propose that blocking kynurenine production or activity can be an efficient approach to specifically limit the growth of colon cancer cells. Here, we describe our findings and new questions for future studies targeted at understanding AHR-independent function of kynurenine, as well as interfering with the enzyme AFMID as a new strategy to target the kynurenine pathway.

Necroptosis, known as programmed necrosis, is a form of caspase-independent, finely regulated cell death with necrotic morphology. Tumor necrosis, foci of necrotic cell death, occurs in advanced solid tumors and is often associated with poor prognosis of cancer patients. While it is well documented that apoptosis plays a key role in tumor regression and the inactivation of apoptosis is pivotal to tumor development, the role of necroptosis in tumorigenesis is still not fully understood as recent studies have reported both tumor-promoting and tumor-suppressing effects of necroptosis. In this short review, we will discuss some recent studies about the role of necroptosis in tumorigenesis and speculate the implications of these findings in future research and potential novel cancer therapy targeting necroptosis.

Recent advances in immunology and cancer research show that fatty acids, their metabolism and their sensing have a crucial role in the biology of many different cell types. Indeed, they are able to affect cellular behaviour with great implications for pathophysiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and agonists/antagonists that are potential therapeutic targets, some of which have already been successfully pursued. Fatty acids can affect the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the balance between anti- and pro-inflammatory signals in immune diseases, such as rheumatoid arthritis, psoriasis, diabetes, obesity and cardiovascular conditions. In the context of cancer biology, fatty acids mainly provide substrates for energy production, which is of crucial importance to meet the energy demands of these highly proliferating cells. Fatty acids can also be involved in a broader transcriptional programme as they trigger signals necessary for tumorigenesis and can confer to cancer cells the ability to migrate and generate distant metastasis. For these reasons, the study of fatty acids represents a new research direction that can generate detailed insight and provide novel tools for the understanding of immune and cancer cell biology, and, more importantly, support the development of novel, efficient and fine-tuned clinical interventions. Here, we review the recent literature focusing on the involvement of fatty acids in the biology of immune cells, with emphasis on T cells, and cancer cells, from sensing and binding, to metabolism and downstream effects in cell signalling.

Eukaryotic cells contain several types of RNA-protein membraneless macro-complexes - ribonucleoprotein (RNP) granules that form by liquid-liquid phase separation. These structures represent biochemical microreactors for a variety of cellular processes and also act as highly accurate sensors of changes in the cellular environment. RNP granules share multiple protein components, however, the connection between spatially separated granules remains surprisingly understudied. Paraspeckles are constitutive nuclear RNP granules whose numbers significantly increase in stressed cells. Our recent work using affinity-purified paraspeckles revealed that another type of RNP granule, cytoplasmic stress granule (SG), acts as an important regulator of stress-induced paraspeckle assembly. Our study demonstrates that despite their residency in different cellular compartments, the two RNP granules are closely connected. This study suggests that nuclear and cytoplasmic RNP granules are integral parts of the intracellular "RNP granule continuum" and that rapid exchange of protein components within this continuum is important for the temporal control of cellular stress responses. It also suggests that cells can tolerate and efficiently handle a certain level of phase separation, which is reflected in the existence of "bursts", or "waves", of RNP granule formation. Our study triggers a number of important questions related to the mechanisms controlling the flow of RNP granule components within the continuum and to the possibility of targeting these mechanisms in human disease.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of death of patients with malignant cancers by 2030. Current options of PDAC treatment are limited and the five-year survival rate is less than 8%, leading to an urgent need to explore innovatively therapeutic strategies. PDAC cells exhibit extensively reprogrammed metabolism to meet their energetic and biomass demands under extremely harsh conditions. The metabolic changes are closely linked to signaling triggered by activation of oncogenes like KRAS as well as inactivation of tumor suppressors. Furthermore, tumor microenvironmental factors including extensive desmoplastic stroma reaction result in series of metabolism remodeling to facilitate PDAC development. In this review, we focus on the dysregulation of metabolism in PDAC and its surrounding microenvironment to explore potential metabolic targets in PDAC therapy.

Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In this review, we discuss recent findings implicating ER and Golgi stress responses in early brain development and provide an overview of microcephaly-associated genes involved in these pathways.

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug's mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315's multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.