bims-meluca 2020-08-16 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–08–16
eight 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

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.
Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer.
The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells.
Comparison of three nutritional scoring systems for outcomes after complete resection of non-small cell lung cancer.
Implications of lipid droplets in lung cancer: Associations with drug resistance.
Different mechanisms of cisplatin resistance development in human lung cancer cells.
Comparison of the amino acid profile between the nontumor and tumor regions in patients with lung cancer.
Metformin andbetter survival in Type 2 Diabetes patients with NSCLC during EGFR-TKI Treatment: implications of miR-146a?

Mol Oncol. 2020 Aug 10.

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Elisabeth Smolle, Petra Leko, Elvira Stacher-Priehse, Luka Brcic, Amin El-Heliebi, Lilli Hofmann, Franz Quehenberger, Andelko Hrzenjak, Helmut H Popper, Horst Olschewski, Katharina Leithner.

  Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.

Keywords:  GLUT1; PCK2; gluconeogenesis; glycolysis; lung cancer

DOI:  https://doi.org/10.1002/1878-0261.12780
Oncology. 2020 Aug 13. 1-8

Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer.

Sook Kyung Do, Sun Ha Choi, Shin Yup Lee, Jin Eun Choi, Hyo-Gyoung Kang, Mi Jeong Hong, Ji Hyun Kim, Sun Ah Baek, Jang Hyuck Lee, Won Kee Lee, Young Woo Do, Eung Bae Lee, Kyung Min Shin, Ji Yun Jeong, Yong Hoon Lee, Hyewon Seo, Seung Soo Yoo, Jaehee Lee, Seung Ick Cha, Chang Ho Kim, Yangki Seok, Sukki Cho, Sanghoon Jheon, Jae Yong Park.

   BACKGROUND: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC).
METHODS: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed.
RESULTS: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54-0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13-4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08-1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10-3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41-1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11-6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17-2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12-6.88, p = 0.03, respectively).
CONCLUSIONS: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

Keywords:  Non-small cell lung cancer; One-carbon metabolism; Polymorphism; Surgery; Survival

DOI:  https://doi.org/10.1159/000509658
Int J Biol Sci. 2020 ;16(14): 2692-2703

The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells.

Bingyu Huang, Zhiyuan Zhou, Jiao Liu, Xin Wu, Xiangyong Li, Qiang He, Peihua Zhang, Xudong Tang.

  Our previous studies have found that human papillomavirus (HPV)-16 E7 oncoprotein promotes epithelial-mesenchymal transition (EMT) and hypoxia-inducible factor-1α (HIF-1α) protein accumulation in non-small cell lung cancer (NSCLC) cells and monoamine oxidase A (MAOA) is highly expressed in NSCLC tissues. Here, we further explored the role of MAOA in HPV-16 E7-induced EMT and HIF-1α protein accumulation in A549 and NCI-H460 NSCLC cells. Our results showed that HPV-16 E7 enhanced MAOA expression in NSCLC cells. Additionally, MAOA knockout inhibited HPV-16 E7-induced migration, invasion, and EMT, and significantly reduced HPV-16 E7-induced ROS generation and HIF-1α protein accumulation via promoting its degradation. Furthermore, MAOA knockout suppressed HPV-16 E7-induced ERK1/2 activation. In vivo, MAOA knockout inhibited tumor growth, metastasis, and the expression of EMT-related markers and HIF-1α proteins induced by HPV-16 E7 in NCI-H460 NSCLC subcutaneous xenograft and in situ intrapulmonary models of nude mice. Taken together, our findings provide evidence that MAOA plays a key role in EMT and HIF-1α protein accumulation induced by HPV-16 E7 in NSCLC cells, suggesting that MAOA may be a potential therapeutic target for HPV-related NSCLC.

Keywords:  epithelial-mesenchymal transition (EMT); human papillomavirus (HPV); hypoxia-inducible factor-1α (HIF-1α); monoamine oxidases A (MAOA); non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.7150/ijbs.46966
J Thorac Cardiovasc Surg. 2020 Jun 29. pii: S0022-5223(20)31751-7. [Epub ahead of print]

Comparison of three nutritional scoring systems for outcomes after complete resection of non-small cell lung cancer.

Mamoru Takahashi, Terumasa Sowa, Hironobu Tokumasu, Tadashi Gomyoda, Harutaro Okada, Sachiko Ota, Yasuji Terada.

   OBJECTIVES: Mounting evidence suggests that preoperative nutritional status can predict postoperative outcomes in patients with non-small cell lung cancer. However, a consensus on the optimal evaluation tool among the various nutritional assessment methods has not been reached. This study aimed at validating the predictive value of 3 nutritional scoring systems for clinical outcomes in patients with completely resected non-small cell lung cancer.
METHODS: We retrospectively reviewed the preoperative data of 475 consecutive patients with completely resected non-small cell lung cancer to assess the following 3 albumin-based nutritional methods: prognostic nutritional index, controlling nutritional status score, and geriatric nutritional risk index.
RESULTS: Receiver operating characteristic curves of the prognostic nutritional index, controlling nutritional status score, and geriatric nutritional risk index identified the optimal cutoff values for predicting the postoperative complications as 47, 2, and 101, respectively. Stratification of patients using these cutoff values indicated a higher postoperative complication rate in the malnutrition group than in the group with proper nutrition (P < .05 for all nutritional assessment methods). Additionally, patients with malnutrition exhibited significantly lower 5-year overall and recurrence-free survivals, regardless of the assessment method (P < .05 for all 3 nutritional assessment methods). Multivariate analyses showed that all 3 nutritional parameters were independent prognostic factors for overall survival after lung resection.
CONCLUSIONS: The 3 nutritional assessment methods we used were found to have high predictive values for postoperative complications and survival. Preoperative nutritional conditioning may improve the postoperative outcomes in patients with resectable non-small cell lung cancer.

Keywords:  controlling nutritional status; geriatric nutritional risk index; non--small cell lung cancer; preoperative nutritional status; prognostic nutritional index

DOI:  https://doi.org/10.1016/j.jtcvs.2020.06.030
Oncol Lett. 2020 Sep;20(3): 2091-2104

Implications of lipid droplets in lung cancer: Associations with drug resistance.

Chunlai Jin, Peng Yuan.

  Cancer cells usually show different metabolic patterns compared with healthy cells due to the reprogramming of metabolic processes. The process of lipid metabolism undergoes notable changes, leading to the accumulation of lipid droplets in cells. Additionally, this phenotype is considered an important marker of cancer cells. Lipid droplets are a highly dynamic type of organelle in the cell, which is composed of a neutral lipid core, a monolayer phospholipid membrane and lipid droplet-related proteins. Lipid droplets are involved in several biological processes, including cell proliferation, apoptosis, lipid metabolism, stress, immunity, signal transduction and protein trafficking. Epidermal growth factor receptor (EGFR)-activating mutations are currently the most effective therapeutic targets for non-small cell lung cancer. Several EGFR tyrosine kinase inhibitors (EGFR-TKIs) that target these mutations, including gefitinib, erlotinib, afatinib and osimertinib, have been widely used clinically. However, the development of acquired resistance has a major impact on the efficacy of these drugs. A number of previous studies have reported that the expression of lipid droplets in the tumor tissues of patients with lung cancer are elevated, whereas the association between elevated numbers of lipid droplets and drug resistance has received little attention. The present review describes the potential association between lipid droplets and drug resistance. Furthermore, the mechanisms and implications of lipid droplet accumulation in cancer cells are analyzed, as wells as the mechanism by which lipid droplets suppress endoplasmic reticulum stress and apoptosis, which are essential for the development and treatment of lung cancer.

Keywords:  drug resistance; epidermal growth factor receptor; lipid droplet; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3892/ol.2020.11769
Biochem Biophys Res Commun. 2020 Aug 08. pii: S0006-291X(20)31427-3. [Epub ahead of print]

Different mechanisms of cisplatin resistance development in human lung cancer cells.

Keisuke Okamoto, Yoshitaka Saito, Katsuya Narumi, Ayako Furugen, Ken Iseki, Masaki Kobayashi.

  Cisplatin (CDDP) is a highly potent and important anticancer drug in lung cancer treatment. Long-term use of an anticancer agent causes resistance in cancer cells, and CDDP resistance involves multiple mechanisms. As the mechanism of resistance development differs depending on the cancer cell types, we aimed to evaluate the detailed mechanism of resistance to CDDP in two types of lung cancer cells: SBC-3 and A549 cells. The CDDP-resistant SBC-3/DDP and A549/DDP cells were established through continuous treatment with a gradually increasing dose of CDDP. The viability of SBC-3/DDP and A549/DDP cells treated with CDDP was 3.68 and 2.08 times higher than that of the respective parental cells. Moreover, SBC-3/DDP cells showed significantly increased cystine/glutamate transporter (xCT) mRNA level, and A549/DDP cells showed markedly increased sex determining region Y-box 2 (SOX2) mRNA level. Moreover, the uptake of cystine, a substrate of xCT, was higher in SBC-3/DDP cells than in SBC-3 cells, and cystine uptake in A549/DDP cells was not different from that in A549 cells. In addition, co-treatment with CDDP and sulfasalazine, an xCT inhibitor, showed lower the concentration of 50% inhibition for cell viability than CDDP alone in SBC-3 and SBC-3/DDP cells, but not in A549 and A549/DDP cells. Furthermore, SBC-3 cells transiently overexpressing xCT were resistant to CDDP, and xCT knockdown in A549/DDP cells did not significantly change the level of SOX2 mRNA and viability of cells upon CDDP treatment. In conclusion, the two lung cancer cell lines showed different mechanisms of resistance to CDDP.

Keywords:  A549; Cisplatin; Resistance; SBC-3; SOX2; xCT

DOI:  https://doi.org/10.1016/j.bbrc.2020.07.040
Am J Cancer Res. 2020 ;10(7): 2145-2159

Comparison of the amino acid profile between the nontumor and tumor regions in patients with lung cancer.

Haruka Namikawa-Kanai, Teruo Miyazaki, Taisuke Matsubara, Shunsuke Shigefuku, Shotaro Ono, Eiji Nakajima, Yukio Morishita, Akira Honda, Kinya Furukawa, Norihiko Ikeda.

Energy metabolism in cancer cells is reprogrammed to meet the energy demands for cell proliferation under strict environments. In addition to the specifically activated metabolism of cancer, including the Warburg effect and glutaminolysis, most amino acids (AAs) are utilized for gluconeogenesis. Significant increases in AAs and energy metabolites in the tumor region occur in gastric and colon cancers. However, a different AA-related energy metabolism may exist in lung cancer because of the abundant blood supply to lung tissue. This study compared the profiles of AAs and their related metabolites in energy metabolism, analyzed by an HPLC-MS/MS system, between tissues from nontumor and tumor regions collected from 14 patients with non-small cell lung cancer (NSCLC). In the energic metabolism precursor categories, the glucogenic AAs, which included the pyruvate precursors (Ser, Gly, Thr, Ala, and Trp), the α-ketoglutarate precursors (Glu, Gln, and Pro) and the succinyl-CoA precursors (Val, Ile, and Met) were significantly increased in the tumor region compared to in the nontumor region. However, no significant differences existed between the two regions in the ketogenic AAs (Leu, Lys, and Tyr). These differences were not observed between the subgroups with and without diabetes mellitus in the two regions. The metabolites on the left-hand side of the TCA cycle were significantly higher in the tumor region, but no differences in metabolites in the right-hand side. The mRNA expressions of major AA transporters and cancer proliferation factors were also significantly increased in the tumor region, compared to these in their counterparts. In lung cancer, glucogenic AAs that are actively transported from circulating fluids would be predominantly utilized for gluconeogenesis, with and without diabetes mellitus. The characteristics of the AA-related metabolism would be associated with tissue-specific cell proliferation in patients with NSCLC.

Keywords: NSCLS; amino acids; energy metabolism; gluconeogenesis; tumor region
Clin Respir J. 2020 Aug 10.

Metformin andbetter survival in Type 2 Diabetes patients with NSCLC during EGFR-TKI Treatment: implications of miR-146a?

Raffaella Mormile.

Type 2 diabetes (T2DM) has been associated with an increased lung cancer risk1,2 .It has been found that poor glycemic control reduces the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients affected by diabetes mellitus1 .NSCLC accounts for approximately 75-85% of all cases of lung cancer3 . Metformin has become the favorite first-line oral blood glucose-lowering agent for the treatment of T2DM4 . It has been demonstrated that metformin exertsanticancer activities in several types of cancer1,2 .

DOI: https://doi.org/10.1111/crj.13254