bims-meluca 2022-03-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–03–06
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

Metformin increases the radiosensitivity of non-small cell lung cancer cells by destabilizing NRF2.
Therapeutic Potential of Glutamine Pathway in Lung Cancer.
Plasma Endoglin is Associated with Favorable Outcome for Pemetrexed-Based Therapy in Advanced Non-Small Cell Lung Cancer.
A case of squamous cell lung cancer treated with anamorelin in combination with a multidisciplinary collaborative approach for treating cancer cachexia.
LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer.
Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?
Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance.

Biochem Pharmacol. 2022 Feb 25. pii: S0006-2952(22)00075-2. [Epub ahead of print] 114981

Metformin increases the radiosensitivity of non-small cell lung cancer cells by destabilizing NRF2.

Xiaohui Sun, Mingxin Dong, Yu Gao, Yan Wang, Liqing Du, Yang Liu, Qin Wang, Kaihua Ji, Ningning He, Jinhan Wang, Manman Zhang, Yeqing Gu, Huijiuan Song, Hezheng Zhai, Li Feng, Chang Xu, Qiang Liu.

  Radiation resistance is an obstacle to the successful treatment of lung cancer. Metformin, a first-line antidiabetic drug, has been studied for its potential use in radiotherapy, as several lines of evidence suggest that metformin enhances radiation sensitivity of cancer cells. However, the underlying mechanisms by which metformin exerts its radiosensitization effects on non-small cell lung cancer (NSCLC) cells remain obscure. Here, we confirmed that metformin increases the radiosensitivity of NSCLC cells and radiation-resistant NSCLC cells. Furthermore, we identified nuclear factor erythroid 2-related factor 2 (NRF2) as a critical target of radiosensitization effect of metformin, as the radiosensitization effect was abolished in NRF2 knockout cells. We also showed that metformin treatment increased the ubiquitination and proteasomal degradation of NRF2 through a KEAP1-independent mechanism. The decrease of NRF2 led to reduced transcription of downstream antioxidant-related proteins, inhibited the initiation of DNA damage repair pathways, and compromised G2/M phase arrest after radiation. In an orthotopic transplanted tumor model in nude mice, metformin treatment reduced NRF2 levels and led to fewer lung tumor nodules. Combination of irradiation further potentiated the antitumor efficacy compared to each of the single treatments. In conclusion, our results suggest that the degradation of NRF2 that is induced by metformin may play a pivotal role in radiosensitizing NSCLC cells and that metformin can be developed as a sensitizer of radiotherapy against lung cancer.

Keywords:  ATR; KEAP1; Metformin; NRF2; NSCLC cells; Radiosensitivity

DOI:  https://doi.org/10.1016/j.bcp.2022.114981
Front Oncol. 2021 ;11 835141

Therapeutic Potential of Glutamine Pathway in Lung Cancer.

Enyu Tang, Siyang Liu, Zhiming Zhang, Rixin Zhang, Dejing Huang, Tong Gao, Tianze Zhang, Guangquan Xu.

  Cancer cells tend to obtain the substances needed for their development depending on altering metabolic characteristics. Among the reorganized metabolic pathways, Glutamine pathway, reprogrammed to be involved in the physiological process including energy supply, biosynthesis and redox homeostasis, occupies an irreplaceable role in tumor cells and has become a hot topic in recent years. Lung cancer currently maintains a high morbidity and mortality rate among all types of tumors and has been a health challenge that researchers have longed to overcome. Therefore, this study aimed to clarify the essential role of glutamine pathway played in the metabolism of lung cancer and its potential therapeutic value in the interventions of lung cancer.

Keywords:  glutaminase; glutamine; glutamine transporter; lung cancer; metabolic reprogramming; target

DOI:  https://doi.org/10.3389/fonc.2021.835141
Cancer Manag Res. 2021 ;13 9305-9318

Plasma Endoglin is Associated with Favorable Outcome for Pemetrexed-Based Therapy in Advanced Non-Small Cell Lung Cancer.

Che-Hsing Li, Jiunn-Liang Ko, Yu-Ping Hsiao, Ming-Hung Tsai, Yen-Chein Lai, I-Lun Hsin, Yu-Ting Kang, Gwo-Tarng Sheu, Wea-Lung Lin, Ming-Fang Wu.

   Purpose: Pemetrexed-based chemotherapy (Pem-C) is the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, limited tumor-associated proteins in blood are available to predict pemetrexed response and/or survival.
Patients and Methods: Plasma samples from three responders and three nonresponders with stage IIIB-IV NSCLC were collected prior to Pem-C and analyzed using Proteome ProfilerTM Human XL Oncology Array to detect 84 oncology-related proteins. The plasma concentrations of cathepsin S, endoglin (ENG), and matrix metalloproteinases 3 and 9 in 71 patients with advanced NSCLC treated with Pem-C were further measured using enzyme-linked immunosorbent assay based on the remarkable differences in the four proteins between responders and nonresponders in the array results.
Results: Pem-C responders had significantly higher ENG levels but not the other three markers than nonresponders (mean ENG level: 27.1 ± 7.4 vs 22.3 ± 6.9, p < 0.01). High ENG concentration was correlated with improved progression-free survival (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.31-0.86, p < 0.01) and overall survival (HR: 0.55, 95% CI: 0.32-0.94, p < 0.05) in patients treated with Pem-C, and the ENG level was an independent factor in our cohort (HR: 0.54, 95% CI: 0.33-0.89, p < 0.05). ENG concentration in Pem-C responders also significantly increased at the time of best response (p < 0.05).
Conclusion: Cumulatively, this study reveals that ENG is correlated with Pem-C responsiveness in patients, which indicates the potential use of plasma ENG levels as a non-invasive biomarker for pemetrexed-based treatment in patients with non-squamous NSCLC.

Keywords:  biomarker; endoglin; non-squamous non-small cell lung cancer; pemetrexed-based therapy; prognostic factor

DOI:  https://doi.org/10.2147/CMAR.S338957
Respir Med Case Rep. 2022 ;36 101609

A case of squamous cell lung cancer treated with anamorelin in combination with a multidisciplinary collaborative approach for treating cancer cachexia.

Yuri Oshima, Hiroyuki Matsuura, Yusuke Sakurai, Kaho Hirai, Eriko Tani, Naoki Yoshimoto, Kenichi Minami, Fumio Yamasaki, Mayu Nishime, Tomonori Hirashima.

  Anamorelin (ANA) is approved for treating cancer cachexia (CCX) in Japan. We report the case of a 69-year-old man with stage IVB squamous cell lung cancer complicated by CCX, having a 13.6% weight loss in 6 months. After chemotherapy was initiated, his weight was further reduced. Therefore, we started ANA combined with a treatment approach by a multidisciplinary collaboration, including nutritionists and physical therapists. After initiation of ANA, the body weight, appetite, psoas muscle index, and physical functions rapidly improved during chemotherapy. ANA administration combined with a multidisciplinary collaboration approach can be an effective supportive therapy against CCX during chemotherapy.

Keywords:  ANA, anamorelin; Anamorelin; BMI, body mass index; BW, body weight; BWL, body weight loss; CCX, cancer cachexia; CT, computed tomography; Cancer cachexia; LBM, lean body mass; Lung cancer; Multidisciplinary collaboration; NSCLC, non-small cell lung cancer; PMI, psoas muscle index

DOI:  https://doi.org/10.1016/j.rmcr.2022.101609
Nat Commun. 2022 Feb 28. 13(1): 1090

LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer.

Christopher W Murray, Jennifer J Brady, Mingqi Han, Hongchen Cai, Min K Tsai, Sarah E Pierce, Ran Cheng, Janos Demeter, David M Feldser, Peter K Jackson, David B Shackelford, Monte M Winslow.

LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.

DOI: https://doi.org/10.1038/s41467-022-28619-8
Anticancer Res. 2022 Mar;42(3): 1487-1493

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?

Chiara Ciccarese, Roberto Iacovelli, Sebastiano Buti, Francesca Primi, Serena Astore, Francesco Massari, Miriam Grazia Ferrara, Giuseppe Palermo, Nazario Foschi, Valerio Iacovelli, Ernesto Rossi, Giovanni Schinzari, Pierluigi Bove, Pierfrancesco Bassi, Emilio Bria, Giampaolo Tortora.

   BACKGROUND/AIM: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients.
PATIENTS AND METHODS: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination.
RESULTS: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate.
CONCLUSION: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination.

Keywords:  Immunotherapy; diabetic cancer patients; immune checkpoint inhibitor; metformin; nivolumab; safety

DOI:  https://doi.org/10.21873/anticanres.15620
Cell Death Dis. 2022 Mar 04. 13(3): 205

Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance.

Peng Liu, Si-Jia Sun, Ying-Jie Ai, Xu Feng, Yi-Min Zheng, Yun Gao, Jin-Ye Zhang, Lei Zhang, Yi-Ping Sun, Yue Xiong, Miao Lin, Hai-Xin Yuan.

Increased glycolysis is a hallmark of tumor, which can provide tumor cells with energy and building blocks to promote cell proliferation. Recent studies have shown that not only the expression of glycolytic genes but also their subcellular localization undergoes a variety of changes to promote development of different types of tumors. In this study, we performed a comprehensive analysis of glycolysis and gluconeogenesis genes based on data from TCGA to identify those with significant tumor-promoting potential across 14 types of tumors. This analysis not only confirms genes that are known to be involved in tumorigenesis, but also reveals a significant correlation of triosephosphate isomerase 1 (TPI1) with poor prognosis, especially in lung adenocarcinoma (LUAD). TPI1 is a glycolytic enzyme that interconverts dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP). We confirm the upregulation of TPI1 expression in clinical LUAD samples and an inverse correlation with the overall patient survival. Knocking down of TPI1 in lung cancer cells significantly reduced cell migration, colony formation, and xenograft tumor growth. Surprisingly, we found that the oncogenic function of TPI1 depends on its translocation to cell nucleus rather than its catalytic activity. Significant accumulation of TPI1 in cell nucleus was observed in LUAD tumor tissues compared with the cytoplasm localization in adjacent normal tissues. Moreover, nuclear translocation of TPI1 is induced by extracellular stress (such as chemotherapy agents and peroxide), which facilitates the chemoresistance of cancer cells. Our study uncovers a novel function of the glycolytic enzyme TPI1 in the LUAD.

DOI: https://doi.org/10.1038/s41419-022-04655-6