bims-meluca 2019-04-21 papers

Elife. 2019 Apr 16. pii: e44235. [Epub ahead of print]8

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.

Mark R Sullivan, Laura V Danai, Caroline A Lewis, Sze Ham Chan, Dan Y Gui, Tenzin Kunchok, Emily A Dennstedt, Matthew G Vander Heiden, Alexander Muir.

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

Keywords: biochemistry; cancer biology; chemical biology; mouse

DOI: https://doi.org/10.7554/eLife.44235

Chem Sci. 2019 Mar 14. 10(10): 3089-3095

Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism.

Zhenzhu Zhu, Zenghui Wang, Changli Zhang, Yanjun Wang, Hongmei Zhang, Zhenji Gan, Zijian Guo, Xiaoyong Wang.

Mitochondria are potential therapeutic targets for anticancer drugs. A series of mitochondrion-targeted monofunctional platinum complexes, [Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2 (OPT), [Pt(meta-PPh3CH2Py)(NH3)2Cl](NO3)2 (MPT), and [Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2 (PPT) (PPh3 = triphenylphosphonium, Py = pyridine), are studied in this article. The antitumor activity and mechanism of action have been investigated in vitro and in vivo as well as on molecular levels. OPT exhibits higher efficacy than cisplatin against A549 lung cancer cells; furthermore, it shows a strong inhibition towards the growth of non-small-cell lung cancer in nude mice. The DNA binding ability of these complexes follows an order of PPT > OPT > MPT. Cellular uptake and distribution studies show that OPT accumulates mainly in mitochondria, while MPT and PPT accumulate more preferentially in nuclei than in mitochondria. As a result, OPT induces remarkable changes in the ultrastructure and membrane of mitochondria, leading to more radical mitochondrial dysfunctions than cisplatin. The release of cytochrome c from mitochondria is more evident for cells treated with OPT than with cisplatin, though the apoptosis of A549 cells induced by OPT is similar to that induced by cisplatin. Disruption to mitochondrial oxidative phosphorylation and glycolysis is involved in the antitumor mechanism of these compounds. The results indicate that in addition to DNA binding, bioenergetic pathways also play crucial roles in the antitumor activity of mitochondrion-targeted monofunctional platinum complexes.

DOI: https://doi.org/10.1039/c8sc04871a

Cancer Sci. 2019 Apr 20.

Repressive role of stabilized HIF1α expression on TGFβ-induced extracellular matrix production in lung cancer cells.

Akira Ando, Naozumi Hashimoto, Koji Sakamoto, Norihito Omote, Shinichi Miyazaki, Yoshio Nakahara, Kazuyoshi Imaizumi, Tsutomu Kawabe, Yoshinori Hasegawa.

Activation of transforming growth factor β (TGFβ) combined with persistent hypoxia are often affecting the tumor microenvironment. Disruption of cadherin/catenin complexes induced by these stimulations yields aberrant extracellular matrix (ECM) production, characteristics of an epithelial-mesenchymal transition (EMT). Hypoxia-inducible factors (HIFs), the hallmark of the response to hypoxia, play differential roles during development of diseases. Recent studies show that localization of cadherin/catenin complexes at the cell membrane might be tightly regulated by protein phosphatase activity. We aimed to investigate the role of stabilized HIF1α expression via protein phosphatase activity on dissociation of the E-cadherin/β-catenin complex and aberrant ECM expression in lung cancer cells under stimulation by TGFβ. By using lung cancer cells treated with HIF1α stabilizers or carrying doxycycline-dependent HIF1α deletion or point mutants, we investigated the role of stabilized HIF1α expression on TGFβ-induced EMT in lung cancer cells. Furthermore, the underlying mechanisms were determined by inhibition of protein phosphatase activity. Persistent stimulation by TGFβ and hypoxia induced the EMT phenotypes in H358 cells in which stabilized HIF1α expression was inhibited. Stabilized HIF1α protein expression inhibited the TGFβ-stimulated appearance of EMT phenotypes across cell types and species, independent of de novo vascular endothelial growth factor A (VEGFA) expression. Inhibition of protein phosphatase A2 activity abrogated the HIF1α-induced repression of TGFβ-stimulated appearance of EMT phenotypes. This is the first study to demonstrate a direct role of stabilized HIF1α expression on inhibition of TGFβ-induced EMT phenotypes in lung cancer cells, in part via protein phosphatase activity. This article is protected by copyright. All rights reserved.

Keywords: HIF1α; TGFβ; epithelial-mesenchymal transition; hypoxia; lung cancer

DOI: https://doi.org/10.1111/cas.14027

Int J Mol Sci. 2019 Apr 16. pii: E1874. [Epub ahead of print]20(8):

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer.

Laura Bonanno, Elisabetta Zulato, Alberto Pavan, Ilaria Attili, Giulia Pasello, PierFranco Conte, Stefano Indraccolo.

Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.

Keywords: LKB1; immunotherapy; lung cancer; treatment response; tumor angiogenesis; tumor metabolism; tumor microenvironment

DOI: https://doi.org/10.3390/ijms20081874

Cell Death Dis. 2019 Apr 15. 10(5): 329

S-nitrosylation of the Peroxiredoxin-2 promotes S-nitrosoglutathione-mediated lung cancer cells apoptosis via AMPK-SIRT1 pathway.

Yihan Zhang, Changning Sun, Guokai Xiao, Hui Shan, Luyao Tang, Yujiao Yi, Wengong Yu, Yuchao Gu.

Protein S-nitrosylation, the redox-based posttranslational modification of a cysteine thiol by the attachment of a nitric oxide (NO) group, is responsible for a variety of signaling effects. Dysregulation of S-nitrosylation may be directly linked to cancer apoptotic resistance and cancer therapy outcomes, emphasizing the importance of S-nitrosylation in cancer. Peroxiredoxin-2 (Prdx2), an antioxidant enzyme, plays an important role in the protection of cancer cells from oxidative radical damage caused by hydrogen dioxide (H2O2), which is a potential target for cancer therapy. Our studies showed that, as an endogenous NO carrier, S-nitrosoglutathione (GSNO) induced apoptosis in lung cancer cells via nitrosylating Prdx2. The nitrosylation of Prdx2 at Cys51 and Cys172 sites disrupted the formation of Prdx2 dimer and repressed the Prdx2 antioxidant activity, causing the accumulation of endogenous H2O2. H2O2 activated AMPK, which then phosphorylated SIRT1 and inhibited its deacetylation activity toward p53 in A549 cells or FOXO1 in NCI-H1299 cells. Taken together, our results elucidate the roles and mechanisms of Prdx2 S-nitrosylation at Cys51 and Cys172 sites in lung cancer cells apoptosis and this finding provides an effective lung cancer treatment strategy for managing aberrant Prdx2 activity in lung cancers.

DOI: https://doi.org/10.1038/s41419-019-1561-x

Oncol Lett. 2019 May;17(5): 4329-4334

AMP-activated protein kinase α1 serves a carcinogenic role via regulation of vascular endothelial growth factor expression in patients with non-small cell lung cancer.

Gong Dao Hui, Wang Yu Xiu, Chen Yong, Chi Bei Yuan, Zhang Jun, Gu Jian Jun, Yang Jun Jun, Xu Xing Xiang, Hu Su Wei, Min Ling Feng.

AMP-activated protein kinase α1 (AMPK α1) is involved in the tumorigenesis of various cancer types. However, the role of AMPK α1 in non-small cell lung cancer (NSCLC) remains unclear. In the present study, 99 NSCLC tumor tissues and paired normal tissues were obtained. The expression levels of AMPK α1 were significantly upregulated in NSCLC tumor tissues compared with those in adjacent non-tumor lung tissues. The patients were further divided into two groups according to their expression levels of AMPK α1 in tumor tissues. The results outlined that overexpression of AMPK α1 was associated with poor prognosis. In addition, vascular endothelial growth factor (VEGF) expression levels were associated with malignant progression in patients with NSCLC. Patients with NSCLC that overexpressed AMPK α1 and VEGF had the worst outcomes. Moreover, AMPK α1 may positively regulate VEGF expression. These results suggest that AMPK α1 serves a carcinogenic role at least in part through the regulation of VEGF expression, and thus represents a potential treatment target in patients with NSCLC.

Keywords: AMPKα1; VEGF; non-small cell lung cancer

DOI: https://doi.org/10.3892/ol.2019.10126