bims-meluca 2020-12-20 papers

Front Oncol. 2020 ;10 578315

Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer.

Jiangang Zhao, Xu Lin, Di Meng, Liping Zeng, Runzhou Zhuang, Sha Huang, Wang Lv, Jian Hu.

Nuclear factor erythroid-2-related factor-2 (NFE2L2/Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in non-small cell lung cancer (NSCLC). Nrf2 activity is associated with poor prognosis in NSCLC. Metabolic reprogramming represents a cancer hallmark. Increasing studies reveal that Nrf2 activation promotes metabolic reprogramming in cancer. In this review, we discuss the underlying mechanisms of Nrf2-mediated metabolic reprogramming and elucidate its role in NSCLC. Inhibition of Nrf2 can alter metabolic processes, thus suppress tumor growth, prevent metastasis, and increase sensitivity to chemotherapy in NSCLC. In conclusion, Nrf2 may serve as a therapeutic target for the treatment of NSCLC.

Keywords: Kelch-like ECH-associated protein 1; metabolic reprogramming; non-small cell lung cancer; nuclear factor erythroid-2–related factor-2; reduction-oxidation balance

DOI: https://doi.org/10.3389/fonc.2020.578315

Cell Death Dis. 2020 Dec 11. 11(12): 1047

SEMG1/2 augment energy metabolism of tumor cells.

Oleg Shuvalov, Alyona Kizenko, Alexey Petukhov, Olga Fedorova, Alexandra Daks, Andrew Bottrill, Anastasiya V Snezhkina, Anna V Kudryavtseva, Nikolai Barlev.

SEMG1 and SEMG2 genes belong to the family of cancer-testis antigens (CTAs), whose expression normally is restricted to male germ cells but is often restored in various malignancies. High levels of SEMG1 and SEMG2 expression are detected in prostate, renal, and lung cancer as well as hemoblastosis. However, the functional importance of both SEMGs proteins in human neoplasms is still largely unknown. In this study, by using a combination of the bioinformatics and various cellular and molecular assays, we have demonstrated that SEMG1 and SEMG2 are frequently expressed in lung cancer clinical samples and cancer cell lines of different origins and are negatively associated with the survival rate of cancer patients. Using the pull-down assay followed by LC-MS/MS mass-spectrometry, we have identified 119 proteins associated with SEMG1 and SEMG2. Among the SEMGs interacting proteins we noticed two critical glycolytic enzymes-pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Importantly, we showed that SEMGs increased the protein level and activity of both PKM2 and LDHA. Further, both SEMGs increased the membrane mitochondrial potential (MMP), glycolysis, respiration, and ROS production in several cancer cell lines. Taken together, these data provide first evidence that SEMGs can up-regulate the energy metabolism of cancer cells, exemplifying their oncogenic features.

DOI: https://doi.org/10.1038/s41419-020-03251-w

Nutr Cancer. 2020 Dec 15. 1-14

Prognostic Significance of the Preoperative Controlled Nutritional Status Score in Lung Cancer Patients Undergoing Surgical Resection.

Jingjing Shao, Jing Li, Xun Lei Zhang, Gaoren Wang.

Several studies have reported the preoperative control nutritional status (CONUT) score as an independent prognostic factor for the prognosis of lung cancer patients. Patients with severe chronic obstructive pulmonary disease usually have high cholesterol levels, cachexia, and muscle atrophy. Abnormal nutritional status and lymphopenia were also related to poor prognosis. We explored the relationship between the preoperative CONUT score and patient prognosis and predicted the efficacy of pembrolizumab in lung cancer treatment. A systematic literature search was performed to identify qualified articles reporting the prognostic prediction potential of CONUT scores in lung cancer patients. A meta-analysis was performed for the association between CONUT scores and survival outcomes and clinic-pathological parameters. Overall, eight articles and 1,220 cases were included. Abnormal preoperative CONUT scores were a poor prognostic factor for elderly lung cancer patients. Finally, higher CONUT scores of pembrolizumab were associated with poor survival. CONUT was an independent prognostic indicator of lung cancer, successfully predicting the efficacy and prognosis of pembrolizumab in lung cancer treatment.

DOI: https://doi.org/10.1080/01635581.2020.1850814

Exp Ther Med. 2021 Feb;21(2): 106

miR-218 inhibits glucose metabolism in non-small cell lung cancer via the NF-κB signaling pathway.

Wenxian Tian, Xiangfei Yuan, Yongna Song, Jianxia Zhai, Haixia Wei, Linna Wang, Dan Li, Qiusheng Chen.

High glucose metabolism is recognized as one of the hallmarks of cancer and increased expression levels of several key factors involved in glucose metabolism have been reported in non-small cell lung cancer (NSCLC). Previous studies showed that microRNA (miR)-218 is reduced in NSCLC, but its function in glucose metabolism in NSCLC is not fully understood. The present study aimed to investigate the effect of miR-218 on glucose metabolism in NSCLC cell lines and the underlying molecular mechanism. The present results suggested that miR-218 reduced glucose consumption, the mechanism of glycolysis and activity in the pentose phosphate pathway. In addition, glucose transporter 1 (GLUT1) was identified to be a direct target of miR-218, while overexpression of GLUT1 did not abolish the effect of miR-218 on glucose metabolism. The present results indicated that phosphorylation of NF-κB p65 was significantly decreased by miR-218 in NSCLC cells and that activation of NF-κB led to the inhibition of miR-218 regulation of glucose metabolism. In conclusion, the present results suggested that miR-218 downregulated glucose metabolism in NSCLC not only by directly targeting GLUT1, but also via the NF-κB signaling pathway.

Keywords: NF-κB; glycolysis; microRNA-218; non-small cell lung cancer; pentose phosphate pathway

DOI: https://doi.org/10.3892/etm.2020.9538

Cancer Discov. 2020 Dec 11.

A Lung Cancer Subtype Depends on the Hexosamine Biosynthesis Pathway.

KRAS/LKB1-comutant NSCLC had high flux through and dependence on the hexosamine biosynthesis pathway.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2020-179

Front Nutr. 2020 ;7 600612

Early Loss of Fat Mass During Chemoradiotherapy Predicts Overall Survival in Locally Advanced Squamous Cell Carcinoma of the Lung, but Not in Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

A C H Willemsen, J H R J Degens, L W J Baijens, A-M C Dingemans, A Hoeben, F J P Hoebers, D K M De Ruysscher, A M W J Schols.

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV-) LAHNSCC patients treated with CRT. Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent. Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13-2.39], p = 0.01 and HR 2.30 [95%CI 1.33-3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC (n = 64) [HR 3.80 [95%CI 1.79-8.06] p ≤ 0.001] but not in HPV- LAHNSCC (n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV- LAHNSCC n = 23), the FM change was -1.4 ± 14.5% and -8.7 ± 9.0% in sNSCLC and HPV- LAHNSCC patients, respectively (p < 0.05). Fat fee mass change was -5.6 ± 6.3% and -4.0 ± 4.3% for sNSCLC and HPV- LAHNSCC, respectively (p = 0.31). Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV- LAHNSCC patients. Early FM loss was prognostic in sNSCLC only.

Keywords: bioelectrical impedance analysis; cachexia; chemoradiotherapy (CRT); hand grip strength (HGS); locally advanced (stage III) non-small cell lung cancer; locally advanced head and neck cancer; weight loss

DOI: https://doi.org/10.3389/fnut.2020.600612