bims-meluca 2018-11-25 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2018–11–25
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism.
Utility Of Molecular Imaging With 2-Deoxy-2-[Fluorine-18] Fluoro-D-Glucose Positron Emission Tomography (18f-Fdg Pet) For Small Cell Lung Cancer (Sclc): A Radiation Oncology Perspective.
Mannose impairs tumour growth and enhances chemotherapy.
CD44v-dependent upregulation of xCT is involved in the acquisition of cisplatin-resistance in human lung cancer A549 cells.
Metabolome-based biomarkers: their potential role in the early detection of lung cancer.
Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening of an in-house small molecule library for anti-lung cancer therapeutics.

Cell Rep. 2018 Nov 20. pii: S2211-1247(18)31722-4. [Epub ahead of print]25(8): 2223-2233.e6

Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism.

Barrett L Updegraff, Xiaorong Zhou, Yabin Guo, Mahesh S Padanad, Pei-Hsuan Chen, Chendong Yang, Jessica Sudderth, Carla Rodriguez-Tirado, Luc Girard, John D Minna, Prashant Mishra, Ralph J DeBerardinis, Kathryn A O'Donnell.

  Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells.

Keywords:  Basigin; CRISPR-mediated genome editing; MCT4; TMPRSS11B; glycolytic metabolism; lactate export; lung cancer; lung squamous cell carcinoma; transmembrane serine protease; transposon mutagenesis

DOI:  https://doi.org/10.1016/j.celrep.2018.10.100
Curr Radiopharm. 2018 Nov 20.

Utility Of Molecular Imaging With 2-Deoxy-2-[Fluorine-18] Fluoro-D-Glucose Positron Emission Tomography (18f-Fdg Pet) For Small Cell Lung Cancer (Sclc): A Radiation Oncology Perspective.

Omer Sager, Ferrat Dincoglan, Selcuk Demiral, Bora Uysal, Hakan Gamsiz, Yelda Elcim, Esin Gundem, Bahar Dirican, Murat Beyzadeoglu.

   BACKGROUND AND OBJECTIVE: Although accounting for a relatively small proportion of all lung cancers, small cell lung cancer (SCLC) remains to be a global health concern with grim prognosis. Radiotherapy (RT) plays a central role in SCLC management either as a curative or palliative therapeutic strategy. There has been considerable progress in RT of SCLC thanks to improved imaging techniques leading to accurate target localization for precise delivery of RT. Positron emission tomography (PET) is increasingly used in oncology practice as a non-invasive molecular imaging modality.
METHODS: Herein, we review the utility of molecular imaging with 2-deoxy-2-[fluorine-18] fluoro-D-glucose PET (18F-FDG PET) for SCLC from a radiation oncology perspective.
RESULTS: There has been extensive research on the utility of PET for SCLC in terms of improved staging, restaging, treatment designation, patient selection for curative/palliative intent, target localization, response assessment, detection of residual/recurrent disease, and prediction of treatment outcomes.
CONCLUSION: PET provides useful functional information as a non-invasive molecular imaging modality and may be exploited to improve management of patients with SCLC. Incorporation of PET/CT in staging of patients with SCLC may aid in optimal treatment allocation for an improved therapeutic ratio. From a radiation oncology perspective, combination of functional and anatomical data provided by integrated PET/CT improves discrimination between atelectasis and tumor, and assists in designation of RT portals with its high accuracy to detect intrathoracic tumor and nodal disease. Utility of molecular imaging for SCLC should be further investigated in prospective randomized trials to acquire higher level of evidence for future potential applications of PET.

Keywords:  18F-FDG PET/CT; 2-deoxy-2-[fluorine-18]fluoro-D-glucose PET; PET/CT; Small cell lung cancer (SCLC); computed tomography (CT); positron emission tomography (PET)

DOI:  https://doi.org/10.2174/1874471012666181120162434
Nature. 2018 Nov 21.

Mannose impairs tumour growth and enhances chemotherapy.

Pablo Sierra Gonzalez, James O'Prey, Simone Cardaci, Valentin J A Barthet, Jun-Ichi Sakamaki, Florian Beaumatin, Antonia Roseweir, David M Gay, Gillian Mackay, Gaurav Malviya, Elżbieta Kania, Shona Ritchie, Alice D Baudot, Barbara Zunino, Agata Mrowinska, Colin Nixon, Darren Ennis, Aoisha Hoyle, David Millan, Iain A McNeish, Owen J Sansom, Joanne Edwards, Kevin M Ryan.

It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.

DOI: https://doi.org/10.1038/s41586-018-0729-3
Biochem Biophys Res Commun. 2018 Nov 15. pii: S0006-291X(18)32469-0. [Epub ahead of print]

CD44v-dependent upregulation of xCT is involved in the acquisition of cisplatin-resistance in human lung cancer A549 cells.

Sayo Horibe, Shoji Kawauchi, Toshihito Tanahashi, Naoto Sasaki, Shigeto Mizuno, Yoshiyuki Rikitake.

  Cisplatin (CDDP) is widely used as an anti-cancer platinum agent but its therapeutic efficacy is limited by acquired drug resistance. To develop a new therapeutic strategy that could overcome this resistance, it is important to characterize CDDP-resistant cancer cells. Here we established human lung cancer A549 cell-derived low- and high-grade CDDP-resistant sublines, termed ACR4 and ACR20 cells, by stepwise increasing CDDP concentrations up to 4 and 20 μM, respectively. ACR4 and ACR20 cells showed 6- and 16-fold higher resistance to CDDP than A549 cells, respectively. Cell migration, invasion, and sphere formation were significantly decreased, whereas expression of the stem cell marker CD44v was increased in order of A549, ACR4, and ACR20 cells. The expression of the cystine-glutamate transporter xCT, which is encoded by SLC7A11, was upregulated because of the increased cell surface expression of CD44v in ACR20 cells. Treatment with the xCT inhibitor salazosulfapyridine and knockdown of SLC7A11 mRNA by a specific siRNA significantly improved sensitivity to CDDP in A549, ACR4, and ACR20 cells. Thus, our results suggest that CD44v overexpression is not involved in cancer stem cell properties but increases xCT expression, which leads to the acquisition of CDDP-resistance. This mechanism may contribute to the development of a new therapeutic strategy that can overcome resistance.

Keywords:  CD44v; Cancer stem cell; Cisplatin; Drug resistance; xCT

DOI:  https://doi.org/10.1016/j.bbrc.2018.11.055
Contemp Oncol (Pozn). 2018 ;22(3): 135-140

Metabolome-based biomarkers: their potential role in the early detection of lung cancer.

Karol Jelonek, Piotr Widłak.

  Lung cancer is the leading cause of cancer-related death worldwide, and a major problem affecting its mortality is the late diagnosis of the majority of cases, where treatment options are limited and overall prognosis is very bad. Currently, a low-dose computed tomography (LD-CT) screening in the high-risk group is the only available diagnostic strategy that could reduce mortality due to this malignancy. However, the LD-CT screening test suffers from a high false positive rate. Hence, complementation of LD-CT examination with blood-based biomarkers is a rational approach to increase efficacy and reduce the cost of early lung cancer screening programs. Several molecular signatures that discriminate between patients with early lung cancer and healthy individuals have been proposed in recent years, which are based on components of serum/plasma metabolome. However, none of these signatures has been validated by independent studies based on material collected during real lung cancer screening. Therefore, the validation of the real diagnostic value of these otherwise promising candidates remains a critical step in this challenging field of cancer diagnostics.

Keywords:  blood metabolomics; lung cancer screening; mass spectrometry; nuclear magnetic resonance

DOI:  https://doi.org/10.5114/wo.2018.78942
Bioorg Med Chem Lett. 2018 Nov 17. pii: S0960-894X(18)30902-8. [Epub ahead of print]

Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening of an in-house small molecule library for anti-lung cancer therapeutics.

Fuyun Guo, Shufen Zhao, Xiao'e Li.

  Pyruvate dehydrogenase kinases (PDKs) are widely over-expressed in various human solid cancers, making them attractive therapeutic targets for cancer treatment. Herein, we report the identification of structurally novel PDKs inhibitors by screening of an in-house small molecule library. Biochemical assay indicated that the identified compounds 1-4 inhibited PDK1 activity with EC50 values of 0.50, 1.99, 4.64, and 0.42 µM, respectively. The ITC analysis suggested that the identified compounds 1-4 were pan-isoform PDK inhibitors, which bound to and inhibited the four PDK isoforms. Moreover, 1-4 dose-dependently reduced pyruvate dehydrogenase complex phosphorylation in NCI-H1975 cell. Molecular docking suggested that the most potent compound 4 docked well in the ATP binding pocket of the four PDK isoforms, forming direct hydrogen bond interactions with the conserved amino acids Thr and Asp in ATP binding pocket of PDKs. The cell viability assay demonstrated that 4 potently blocked NCI-H1975 cell proliferation (IC50 = 3.32 µM), but had little effect on human normal lung cell MRC-5 even with the tested concentration up to 40 µM. All the data demonstrated that 4 was a promising lead for the development of structurally novel PDKs inhibitor for the cancer treatment.

Keywords:  Anticancer; Biochemical assay; Proliferation; Pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1016/j.bmcl.2018.11.035