bims-meluca 2021-06-13 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–06–13
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

Metabolic reprograming of antioxidant defense: a precision medicine perspective for radiotherapy of lung cancer?
Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer.
Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer.
Prognostic Significance of SUVmax Combined With Lactate Dehydrogenase in Advanced Lung Cancer Patients Treated With Immune Checkpoint Inhibitor Plus Chemotherapy: A Retrospective Study.
Hyperbaric oxygen suppressed tumor progression through the improvement of tumor hypoxia and induction of tumor apoptosis in A549-cell-transferred lung cancer.
Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.

Biochem Soc Trans. 2021 Jun 10. pii: BST20200866. [Epub ahead of print]

Metabolic reprograming of antioxidant defense: a precision medicine perspective for radiotherapy of lung cancer?

Johann Matschke, Safa Larafa, Verena Jendrossek.

  Radiotherapy plays a key role in the management of lung cancer patients in curative and palliative settings. Traditionally, radiotherapy was either given alone or in combination with surgery, classical cytotoxic chemotherapy, or both. Technical and physical innovations achieved during the last two decades have helped to enhance the accuracy of radiotherapy dose delivery and have facilitated geometric radiotherapy individualization. Furthermore, multimodal combinations with molecularly tailored drugs or immunotherapy yielded promising survival benefits in selected patients. Yet high locoregional failure rates and frequent development of metastases still limit the patient outcome. One major obstacle to successful treatment is the high molecular heterogeneity observed in lung cancer. So far, clinical radiotherapy does not routinely use the knowledge on molecular subtypes with regard to therapy individualization and predictive biomarkers are missing. Herein, altered cancer metabolism has attracted novel attention during recent years as it promotes tumor growth and progression as well as resistance to anticancer therapies. The present perspective will exemplarily highlight how clinically relevant molecular subtypes defined by co-occurring somatic mutations in KRAS-driven lung cancer impact the metabolic phenotype of cancer cells, how the metabolic phenotype supports intrinsic radioresistance by the improved antioxidant defense, and also discuss potential subtype-specific actionable metabolic vulnerabilities. Understanding metabolic phenotypes of radioresistance and metabolic bottlenecks of cancer cells undergoing radiotherapy in a cancer-specific context will offer largely unexploited future avenues for biological individualization and optimization of radiotherapy. Transcriptional profiles will provide additional benefit in defining metabolic phenotypes associated with radioresistance, particularly in cases, where such dependencies cannot be identified by specific somatic mutations.

Keywords:  antioxidant defense; irradiation; personalized medicine; radiotherapy; tumor metabolism

DOI:  https://doi.org/10.1042/BST20200866
Mol Med Rep. 2021 Aug;pii: 560. [Epub ahead of print]24(2):

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer.

Liying Sha, Zhiqiang Lv, Yujun Liu, Yun Zhang, Xin Sui, Teng Wang, Hui Zhang.

  Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit‑8 (CCK‑8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription‑quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose‑dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.

Keywords:  6‑biphosphatase 2; 6‑phosphofructo‑2‑ kinase/fructose‑2; Warburg effect; lung cancer; migration; shikonin

DOI:  https://doi.org/10.3892/mmr.2021.12199
Front Mol Biosci. 2021 ;8 678753

Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer.

Xiaoqun Nie, Liliang Xia, Fang Gao, Lixia Liu, Yi Yang, Yingying Chen, Huangqi Duan, Yaxian Yao, Zhiwei Chen, Shun Lu, Ying Wang, Chen Yang.

  Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC. Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2-3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis. Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027-0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039-0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040-0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009-0.762, p = 0.028). Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.

Keywords:  immune checkpoint inhibitors; metabolite biomarker; non-small cell lung cancer; non-targeted metabolomics; serum metabolomics

DOI:  https://doi.org/10.3389/fmolb.2021.678753
Front Oncol. 2021 ;11 652312

Prognostic Significance of SUVmax Combined With Lactate Dehydrogenase in Advanced Lung Cancer Patients Treated With Immune Checkpoint Inhibitor Plus Chemotherapy: A Retrospective Study.

Linping Ke, Lu Wang, Jinming Yu, Xue Meng.

   Purpose: This research aims to investigate the predictive capacity of PET/CT quantitative parameters combined with haematological parameters in advanced lung cancer patients treated with immune checkpoint inhibitor (ICI) plus chemotherapy.
Methods: A total of 120 patients who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were enrolled before therapy. The following parameters were calculated: the maximum, mean, and peak standardized uptake value (SUVmax, SUVmean, and SUVpeak, respectively); total tumour volume (MTV) and total lesion glycolysis (TLG); and whole-body metabolic values (MTVwb, TLGwb, SUVmeanwb, and SUVmaxwb). Lactate dehydrogenase (LDH) levels, absolute neutrophil count, absolute platelet count, albumin levels and derived neutrophil to lymphocyte ratio (dNLR) were also computed. The associations between the variables and therapy outcome (evaluated by iRECIST) were analyzed.
Results: Based on iRECIST, 32 of 120 patients showed iPD, 43 iSD, 36 iPR and 9 iCR. Multivariate analysis found that SUVmax, MTVwb, LDH and absolute platelet count were associated with treatment response (P =0.015, P =0.005, P <0.001 and P =0.015, respectively). Kaplan-Meier survival analyses showed that SUVmax ≥11.42 and LDH ≥245 U/L were associated with shorter OS (P = 0.001 and P = 0.004, respectively). Multivariate Cox regression revealed that SUVmax and LDH alone were not correlated with survival prognosis (p>0.05), but the combination of SUVmax and LDH was independently associated with OS (P=0.015, P=0.001, respectively). The median survival time (MST) for the low (LDH<245 and SUVmax<11.42), intermediate(LDH<245 or SUVmax<11.42), and high(SUVmax≥11.42 and LDH≥245) groups was 24.10 months (95% CI: 19.43 to 28.77), 17.41 months (95% CI: 15.83 to 18.99), and 13.76 months (95% CI: 12.51 to 15.02), respectively.
Conclusion: This study identified that SUVmax plus LDH correlated with the survival outcome in patients with advanced lung cancer receiving PD-1/PD-L1 blockade plus chemotherapy.

Keywords:  SUVmax; hematology; immunotherapy; lung cancer; prognosis

DOI:  https://doi.org/10.3389/fonc.2021.652312
Sci Rep. 2021 Jun 08. 11(1): 12033

Hyperbaric oxygen suppressed tumor progression through the improvement of tumor hypoxia and induction of tumor apoptosis in A549-cell-transferred lung cancer.

Shao-Yuan Chen, Koichi Tsuneyama, Mao-Hsiung Yen, Jiunn-Tay Lee, Jiun-Liang Chen, Shih-Ming Huang.

Tumor cells have long been recognized as a relative contraindication to hyperbaric oxygen treatment (HBOT) since HBOT might enhance progressive cancer growth. However, in an oxygen deficit condition, tumor cells are more progressive and can be metastatic. HBOT increasing in oxygen partial pressure may benefit tumor suppression. In this study, we investigated the effects of HBOT on solid tumors, such as lung cancer. Non-small cell human lung carcinoma A549-cell-transferred severe combined immunodeficiency mice (SCID) mice were selected as an in vivo model to detect the potential mechanism of HBOT in lung tumors. HBOT not only improved tumor hypoxia but also suppressed tumor growth in murine xenograft tumor models. Platelet endothelial cell adhesion molecule (PECAM-1/CD31) was significantly increased after HBOT. Immunostaining of cleaved caspase-3 was demonstrated and apoptotic tumor cells with nuclear debris were aggregated starting on the 14th-day after HBOT. In vitro, HBOT suppressed the growth of A549 cells in a time-dependent manner and immediately downregulated the expression of p53 protein after HBOT in A549 cells. Furthermore, HBOT-reduced p53 protein could be rescued by a proteasome degradation inhibitor, but not an autophagy inhibitor in A549 cells. Our results demonstrated that HBOT improved tissue angiogenesis, tumor hypoxia and increased tumor apoptosis to lung cancer cells in murine xenograft tumor models, through modifying the tumor hypoxic microenvironment. HBOT will merit further cancer therapy as an adjuvant treatment for solid tumors, such as lung cancer.

DOI: https://doi.org/10.1038/s41598-021-91454-2
Cancer Immunol Immunother. 2021 Jun 05.

Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.

Masato Karayama, Naoki Inui, Yusuke Inoue, Katsuhiro Yoshimura, Kazutaka Mori, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Tomoyuki Fujisawa, Noriyuki Enomoto, Yutaro Nakamura, Kazuhiro Asada, Tomohiro Uto, Masato Fujii, Takashi Matsui, Shun Matsuura, Dai Hashimoto, Mikio Toyoshima, Hideki Kusagaya, Hiroyuki Matsuda, Nao Inami, Yusuke Kaida, Mitsuru Niwa, Yasuhiro Ito, Takafumi Suda.

   BACKGROUND: Lipids have immunomodulatory functions and the potential to affect cancer immunity.
METHODS: The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab.
RESULTS: When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid.
CONCLUSIONS: Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

Keywords:  Anti-programmed death-1 therapy; Immune checkpoint inhibitor; Immunometabolism; Lipid; Metabolism

DOI:  https://doi.org/10.1007/s00262-021-02979-4