bims-stacyt 2019-12-29 papers

Int J Mol Sci. 2019 Dec 25. pii: E169. [Epub ahead of print]21(1):

Endoplasmic Reticulum Stress Pathway, the Unfolded Protein Response, Modulates Immune Function in the Tumor Microenvironment to Impact Tumor Progression and Therapeutic Response.

Manuel U Ramirez, Salvador R Hernandez, David R Soto-Pantoja, Katherine L Cook.

Despite advances in cancer therapy, several persistent issues remain. These include cancer recurrence, effective targeting of aggressive or therapy-resistant cancers, and selective treatments for transformed cells. This review evaluates the current findings and highlights the potential of targeting the unfolded protein response to treat cancer. The unfolded protein response, an evolutionarily conserved pathway in all eukaryotes, is initiated in response to misfolded proteins accumulating within the lumen of the endoplasmic reticulum. This pathway is initially cytoprotective, allowing cells to survive stressful events; however, prolonged activation of the unfolded protein response also activates apoptotic responses. This balance is key in successful mammalian immune response and inducing cell death in malignant cells. We discuss how the unfolded protein response affects cancer progression, survival, and immune response to cancer cells. The literature shows that targeting the unfolded protein response as a monotherapy or in combination with chemotherapy or immunotherapies increases the efficacy of these drugs; however, systemic unfolded protein response targeting may yield deleterious effects on immune cell function and should be taken into consideration. The material in this review shows the promise of both approaches, each of which merits further research.

Keywords: Activating transcription factor 6 (ATF6); Glucose-regulated protein 78 (GRP78); Inositol-requiring enzyme 1 (IRE1); PKR-like endoplasmic reticulum kinase (PERK); T cell; immune cells; macrophage; tumor microenvironment; unfolded protein response

DOI: https://doi.org/10.3390/ijms21010169

Biochem Pharmacol. 2019 Dec 20. pii: S0006-2952(19)30474-5. [Epub ahead of print] 113775

Hydrogen sulfide modulates epithelial-mesenchymal transition and angiogenesis in non-small cell lung cancer via HIF-1α activation.

Mingqi Wang, Jiaqing Yan, Xinyu Cao, Peiyan Hua, Zhengqiang Li.

Hydrogen sulfide (H2S) has been frequently implicated in tumor progression. However, the exact regulation mechanism of H2S in human non-small cell lung cancer (NSCLC) has not been fully elucidated. Here, analysis of NSCLC biopsies and adjacent non-tumor tissues revealed selectively high levels of endogenous H2S-producing enzymes, cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). Similarly, quantitative real-time PCR and western blot results showed that NSCLC cell lines (A549, 95D) expressed higher levels of CBS, CSE and MPST in mRNA and enzyme proteins, respectively. Moreover, NSCLC cell lines produced more H2S than did the normal lung epithelial cell line BEAS-2B. H2S was further detected to induce NSCLC migration and invasion, as well as the epithelial mesenchymal transition (EMT) process. Small interfering RNA (siRNA) silencing of CBS or CSE activity reduced proliferation and metastasis potential of tumor cells. In addition, H2S modulated hypoxia-inducible factor-1α (HIF-1α) to stimulate vascular endothelial growth factor (VEGF) expression, which contributes to tumor angiogenesis. Treatment of nude mice with pharmacological inhibition of CBS or CSE activity decreased xenograft growth and suppressed angiogenesis. Collectively, these results indicate H2S plays an important part in NSCLC growth and angiogenesis by HIF-1α activation, which potentially provide new insight in therapeutic strategies.

Keywords: Hydrogen sulfide; angiogenesis; epithelial-mesenchymal transition; hypoxia-inducible factor-1α; non-small cell lung cancer

DOI: https://doi.org/10.1016/j.bcp.2019.113775

Cell Metab. 2019 Dec 12. pii: S1550-4131(19)30663-1. [Epub ahead of print]

Glutamine Links Obesity to Inflammation in Human White Adipose Tissue.

While obesity and associated metabolic complications are linked to inflammation of white adipose tissue (WAT), the causal factors remain unclear. We hypothesized that the local metabolic environment could be an important determinant. To this end, we compared metabolites released from WAT of 81 obese and non-obese women. This identified glutamine to be downregulated in obesity and inversely associated with a pernicious WAT phenotype. Glutamine administration in vitro and in vivo attenuated both pro-inflammatory gene and protein levels in adipocytes and WAT and macrophage infiltration in WAT. Metabolomic and bioenergetic analyses in human adipocytes suggested that glutamine attenuated glycolysis and reduced uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) levels. UDP-GlcNAc is the substrate for the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) mediated by the enzyme O-GlcNAc transferase. Functional studies in human adipocytes established a mechanistic link between reduced glutamine, O-GlcNAcylation of nuclear proteins, and a pro-inflammatory transcriptional response. Altogether, glutamine metabolism is linked to WAT inflammation in obesity.

Keywords: adipocyte; adipokine; epigenetics; inflammation; leukocyte; macrophage; metabolomics; obesity

DOI: https://doi.org/10.1016/j.cmet.2019.11.019