bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒03‒24
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Lung Cancer. 2019 Apr;pii: S0169-5002(19)30343-5. [Epub ahead of print]130 169-178
    Carneiro-Lobo TC, Scalabrini LC, Magalhães LDS, Cardeal LB, Rodrigues FS, Dos Santos EO, Baldwin AS, Levantini E, Giordano RJ, Bassères DS.
      OBJECTIVES: The ability of tumor cells to drive angiogenesis is an important cancer hallmark that positively correlates with metastatic potential and poor prognosis. Therefore, targeting angiogenesis is a rational therapeutic approach and dissecting proangiogenic pathways is important, particularly for malignancies driven by oncogenic KRAS, which are widespread and lack effective targeted therapies. Based on published studies showing that oncogenic RAS promotes angiogenesis by upregulating the proangiogenic NF-κB target genes IL-8 and VEGF, that NF-κB activation by KRAS requires the IKKβ kinase, and that targeting IKKβ reduces KRAS-induced lung tumor growth in vivo, but has limited effects on cell growth in vitro, we hypothesized that IKKβ targeting would reduce lung tumor growth by inhibiting KRAS-induced angiogenesis.MATERIALS AND METHODS: To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines either by siRNA-mediated transfection or by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor, and used in vitro and in vivo assays to evaluate angiogenesis.
    RESULTS AND CONCLUSIONS: Both pharmacological and siRNA-mediated IKKβ targeting in lung cells reduced expression and secretion of NF-κB-regulated proangiogenic factors IL-8 and VEGF. Moreover, conditioned media from IKKβ-targeted lung cells reduced human umbilical vein endothelial cell (HUVEC) migration, invasion and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and vascularity in vivo. Finally, IKKβ inhibition also affects endothelial cell function in a cancer-independent manner, as IKKβ inhibition reduced pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Taken together, these results provide a novel mechanistic understanding of how the IKKβ pathway affects human lung tumorigenesis, indicating that IKKβ promotes KRAS-induced angiogenesis both by cancer cell-intrinsic and cancer cell-independent mechanisms, which strongly suggests IKKβ inhibition as a promising antiangiogenic approach to be explored for KRAS-induced lung cancer therapy.
    Keywords:  Angiogenesis; IKKβ; IL-8; KRAS; Lung cancer; Therapeutic target; VEGF
  2. Mol Cancer Res. 2019 Mar 18. pii: molcanres.1025.2018. [Epub ahead of print]
    Efimova EV, Appelbe OK, Ricco N, Lee SS, Liu Y, Wolfgeher DJ, Collins TN, Flor AC, Ramamurthy A, Warrington S, Bindokas VP, Kron SJ.
      The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism common in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein post-translational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DNA-damage response pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase (OGA) or simply treating animals with GlcNAc, protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase (OGT) activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DNA damage response, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: Finding that the hexosamine biosynthetic pathway, via its impact on protein O-GlcNAcylation, is a key determinant of the DNA damage response in cancer provides a mechanistic link between metabolic reprogramming, genomic instability and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.
  3. Curr Diab Rep. 2019 Mar 19. 19(5): 21
    Bonacina F, Baragetti A, Catapano AL, Norata GD.
      PURPOSE OF REVIEW: Metabolic reprogramming is increasingly recognized as an essential trait of functional activation of immune cells. Here, we describe the link between immuno-metabolism, diabetes, and diabetic nephropathy.RECENT FINDINGS: Crosstalk between cellular metabolic functions and immune activation occurs when plasma levels of glucose, triglycerides, and free fatty acids increase, thus promoting systemic low-grade inflammation that further boosts the development of metabolic complications. In the long run, this settles an "apparent paradox," where, despite excessive inflammation, the immune system is suppressed, further promoting progression to end-stage renal disease (ESRD) and predisposing to premature deaths from infections and cardiovascular diseases. Reviewing the effects of diabetes treatments on immuno-inflammatory responses suggests that the benefit of these drugs might extend beyond the simple control of glucose homeostasis. Hyperglycemia and dyslipidemia correlate with enhancement of the immuno-inflammatory response that can promote and worsen metabolic diseases and support the progression toward ESRD. The identification of cellular checkpoints that modulate the immuno-metabolic machinery of immune cells opens new venues for metabolic drugs.
    Keywords:  Diabetes; Immune response; Kidney disease; Metabolism
  4. Biomed Pharmacother. 2019 Mar 13. pii: S0753-3322(18)38086-7. [Epub ahead of print]113 108705
    Zhang H, Wei X, Lu S, Lin X, Huang J, Chen L, Huang X, Jiang L, Li Y, Qin L, Wei J, Huang R.
      BACKGROUND: Hyperglycemia stimulated epithelial-mesenchymal transition (EMT) plays a critical role in initiating and progressing renal fibrosis in diabetic kidney disease (DKD). It is crucial to explore novel renal protective drugs for the treatment of DKD.OBJECTIVE: The present study is to confirm our hypothesis and to accumulate the information for the application of DMDD (2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione) as a novel therapeutic agent to potentially inhibit renal fibrogenesis and EMT in the DKD.
    METHODS: High glucose induced renal proximal tubular epithelial cell line (HK-2 cells) was cultured and treated with DMDD. The cell viability and DMDD cytotoxicity were assessed by CCK8. Immunofluorescence was used for detection of TLR4 and downstream protein in normal and high glucose induced HK-2 cells. HK-2 cells were transfected with lentivirus codifying for BAMBI (BMP and activin membrane bound inhibitor) and interfering RNA for determination of the effect of BAMBI over-expression and silencing, respectively. TLR4-BAMBI-Smad2/3 pathway was analyzed by means of RT-PCR and western blot.
    RESULTS: A high concentration (60mM) of glucose induced significant EMT process and TLR4 expression was increased obviously in this circumstance. DMDD inhibited high expressions of TLR4 and Smad2/3 in HG induced cells and decreased the expression of BAMBI. In addition, the effects of decreased BAMBI expression and increased Smad2/3 expression in HG cultured cells were reversed in the cells of TAK-242 (TLR4 signaling inhibitor) intervention. BAMBI gene silencing dramatically increased EMT process and the over-expression of BAMBI was opposite in HK-2 cells with HG condition. These observations of EMT were ameliorated when the HK-2 cells were pre-treated with DMDD.
    CONCLUSIONS: Our study demonstrates that DMDD treatment improves EMT in the HG induced HK-2 cells. In addition, DMDD significantly inhibits EMT by TLR4-BAMBI-Smad2/3 pathway, which hints that DMDD may be an alternative approach in diabetic renal injury.
    Keywords:  DMDD; Diabetic kidney disease; epithelial–mesenchymal transition
  5. FASEB J. 2019 Mar 20. fj201802799R
    Pin F, Novinger LJ, Huot JR, Harris RA, Couch ME, O'Connell TM, Bonetto A.
      Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
    Keywords:  C2C12 myotubes; chemotherapy; energy metabolism; mitochondria; skeletal muscle atrophy