bims-meluca 2019-12-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–12–01
seven 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

LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective.
The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells.
Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.
Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes.
Prognostic and therapeutic potential of Adenylate kinase 2 in lung adenocarcinoma.
CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1.
A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells.

Oxid Med Cell Longev. 2019 ;2019 8730816

LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective.

Francesco Ciccarese, Elisabetta Zulato, Stefano Indraccolo.

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (LKB1) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.

DOI: https://doi.org/10.1155/2019/8730816
Sci Rep. 2019 Nov 27. 9(1): 17639

The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells.

Matheus Molina Silva, Clarissa Ribeiro Reily Rocha, Gabriela Sarti Kinker, Alessandra Luiza Pelegrini, Carlos Frederico Martins Menck.

Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.

DOI: https://doi.org/10.1038/s41598-019-54065-6
Neoplasia. 2019 Nov 22. pii: S1476-5586(19)30396-3. [Epub ahead of print]22(1): 33-46

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.

Jiangtao Sun, Guifang Li, Yiwen Liu, Mingyang Ma, Kaifang Song, Huaxu Li, Daxing Zhu, XiaoJun Tang, Jinyu Kong, Xiang Yuan.

Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targeted therapy suggests that mitochondrial targeting should be synthetically lethal using established cytotoxic therapies. Accordingly, loss of the phenotype present in resistant CSC clones either by targeting the energy metabolism with tigecycline, a mitochondrial DNA-translation inhibitor, or tenovin-6 (TV-6), a SIRT1 inhibitor, inhibited their dependency on mitochondrial oxidative phosphorylation (mtOXPHOS) and sensitized them for a more pronounced and long-lasting TKI therapeutic effect. The results specifically demonstrated that combined therapy with TV-6 and gefitinib resulted in tumor regression in xenograft mouse models, whereas administration of a single agent showed no such efficacy. Importantly, combined treatment with TV-6 also decreased the effective dose of gefitinib necessary for treatment response. Clinical analysis demonstrated that high-profile SIRT1 and mtOXPHOS proteins were associated with recurrence and poor prognosis in LAD patients. These observations support the CSC hypothesis for cancer relapse and advocate use of mitochondria-targeting inhibitors as part of combinatorial therapy in a variety of clinical settings, as well as for reducing first-line TKI dosage in LAD patients.

DOI: https://doi.org/10.1016/j.neo.2019.10.006
J Cell Mol Med. 2019 Nov 28.

Down-regulation of MTHFD2 inhibits NSCLC progression by suppressing cycle-related genes.

Chang Yu, Lehe Yang, Mengsi Cai, Feng Zhou, Sisi Xiao, Yaozhe Li, Tingting Wan, Dezhi Cheng, Liangxing Wang, Chengguang Zhao, Xiaoying Huang.

  Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme located in the mitochondria. It has been reported to be overexpressed in several malignancies. However, the relationship between the expression of MTHFD2 and non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that MTHFD2 was significantly overexpressed in NSCLC tissues and cell lines. Knockdown of MTHFD2 resulted in reduced cell growth and tumorigenicity in vitro and in vivo. Besides, the mRNA and protein expression level of cell cycle genes, such as CCNA2, MCM7 and SKP2, was decreased in MTHFD2 knockdown H1299 cells. Our results indicate that the inhibitory effect of MTHFD2 knockdown on NSCLC may be mediated via suppressing cell cycle-related genes. These findings delineate the role of MTHFD2 in the development of NSCLC and may have potential applications in the treatment of NSCLC.

Keywords:  bioinformatics; cell cycle; methylenetetrahydrofolate dehydrogenase 2; non-small cell lung cancer

DOI:  https://doi.org/10.1111/jcmm.14844
Sci Rep. 2019 Nov 28. 9(1): 17757

Prognostic and therapeutic potential of Adenylate kinase 2 in lung adenocarcinoma.

Huibin Liu, Yan Pu, Quhai Amina, Qiang Wang, Mengmeng Zhang, Jianzhong Song, Jun Guo, Mahmut Mardan.

Adenylate kinase 2 (AK2), an isoenzyme of the AK family, may have momentous extra-mitochondrial functions, especially in tumourigenesis in addition to the well-known control of energy metabolism. In this study, we provided the first evidence that AK2 is overexpressed in lung adenocarcinoma. The positive expression of AK2 is associated with tumor progression, and poor survival in patients with pulmonary adenocarcinoma. Knockdown of AK2 could suppress proliferation, migration, and invasion as well as induce apoptosis and autophagy in human lung adenocarcinoma cells. Remarkably, silencing AK2 exerted the greater tumor suppression roles when combined with hydroxychloroquine, an effective autophagy inhibitor, in vitro and in xenografts mouse models. Our data have probably provided preclinical proof that systematic inhibition of AK2 and autophagy could be therapeutically effective on lung cancer.

DOI: https://doi.org/10.1038/s41598-019-53594-4
Cell Death Dis. 2019 Nov 25. 10(12): 885

CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1.

Jiayu Zhou, Shizhen Zhang, Zhoumiao Chen, Zhengfu He, Yong Xu, Zhijun Li.

Lung adenocarcinoma (LUAD) has long been one of the predominant reasons for the global cancer-linked mortality. The tumor progression is shown by several studies to be promoted by increased glycolysis. Enolase 1 (ENO1), as a glycolysis enzyme, performs pivotal role in glucose metabolism and contributes to tumor progression of numerous cancers. Circular RNAs (circRNAs) are catching increasing attentions for their surging roles in regulating gene expression in cancers. Our work is to uncover the regulatory mechanism circ-ENO1 on its host gene ENO1 and its function in glycolysis and tumor progression. Circ-ENO1 and its host gene ENO1 were identified to be upregulated in LUAD cells. Functionally, silencing circ-ENO1 retarded glycolysis, inhibited proliferation, migration and EMT, induced apoptosis. The cytoplasmic localization of circ-ENO1 was determined by FISH and subcellular fractionation. Mechanistically, circ-ENO1 acted as a ceRNA to interact with miR-22-3p and upregulate ENO1 expression. In vivo experiments certified that circ-ENO1 drove tumor growth and metastasis in vivo. In summary, current study elucidated that circ-ENO1 promoted glycolysis and tumor progression in LUAD by miR-22-3p/ENO1 axis, indicating circ-ENO1 as a promising treatment target for LUAD patients.

DOI: https://doi.org/10.1038/s41419-019-2127-7
Nat Commun. 2019 Nov 29. 10(1): 5444

A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells.

Chiara Ghezzi, Alicia Wong, Bao Ying Chen, Bernard Ribalet, Robert Damoiseaux, Peter M Clark.

Elevated glucose consumption is fundamental to cancer, but selectively targeting this pathway is challenging. We develop a high-throughput assay for measuring glucose consumption and use it to screen non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indicate that our high-throughput assay can identify compounds that regulate glucose consumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway.

DOI: https://doi.org/10.1038/s41467-019-13334-8