bims-meluca 2020-02-02 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–02–02
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

PINK1 depletion sensitizes non-small cell lung cancer to glycolytic inhibitor 3-bromopyruvate: Involvement of ROS and mitophagy.
Metabolic Responses to Metformin in Inoperable Early-stage Non-Small Cell Lung Cancer Treated With Stereotactic Radiotherapy: Results of a Randomized Phase II Clinical Trial.
PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.
Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis.
The GTPase KRAS suppresses the P53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells.
AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics.
Accuracy of predictive equations versus indirect calorimetry for the evaluation of energy expenditure in cancer patients with solid tumors - An integrative systematic review study.
Preoperative Immune-Nutritional Abnormality Predicts Poor Outcome in Elderly Non-Small-Cell Lung Cancer Patients with Comorbidities.

Pharmacol Rep. 2019 Nov;71(6): 1184-1189

PINK1 depletion sensitizes non-small cell lung cancer to glycolytic inhibitor 3-bromopyruvate: Involvement of ROS and mitophagy.

Katherine Dai, Daniel P Radin, Donna Leonardi.

   BACKGROUND: Despite significant strides in understanding the pathophysiology of non-small cell lung cancer (NSCLC), these neoplasms typically present with intrinsic chemo- and radiotherapeutic resistance. Transcriptomic analyses of patient NSCLC tumors stratified by survival times have identified the PTEN-induced putative kinase 1 (PINK1 ) as a molecular governor of tumor aggressiveness and patient survival time. PINK1 has been shown to confer neuroprotection in models of Parkinson Disease by ensuring proper mitochondrial turnover (mitophagy), the upkeep of ATP production and sequestering of reactive oxygen species (ROS).
METHODS: We utilized an shRNA against PINK1 and the glycolytic inhibitor 3-BP to assess effects on NSCLC viability via MTS cell viability assay. ATP levels, caspase-9 activation, mitophagy and ROS production were determined with standardly available kits. Cytochrome c cellular localization and phosphorylated parkin levels were determined using an ELISA.
RESULTS: Our results demonstrate that PINK1 depletion in the NSCLC cell line A549 via shRNA, reduced cancer cell proliferation, increased cell death, reduced ATP production, inhibited mitophagy and increased ROS and caspase-9-dependent apoptosis. PINK1 depleted cells were more susceptible to the glycolytic inhibitor 3-bromopyruvate (3-BP), which further perturbed ATP production. PINK1 depletion and 3-BP synergistically increased ROS production, caspase-9-dependent apoptosis and additively repressed mitophagy.
CONCLUSIONS: These results suggest that PINK1 depletion alters energetic metabolism and confers sensitivity to agents that inhibit glycolysis. Targeting accelerated tumor cell metabolism may prove useful in the clinical setting while sparing non-malignant tissue.

Keywords:  3-bromopyruvate; Mitophagy; Parkin; Pink1; ROS

DOI:  https://doi.org/10.1016/j.pharep.2019.08.002
Am J Clin Oncol. 2020 Jan 27.

Metabolic Responses to Metformin in Inoperable Early-stage Non-Small Cell Lung Cancer Treated With Stereotactic Radiotherapy: Results of a Randomized Phase II Clinical Trial.

Stephen G Chun, Zhongxing Liao, Melenda D Jeter, Joe Y Chang, Steven H Lin, Ritsuko U Komaki, Thomas M Guerrero, Ray C Mayo, Bobby M Korah, Suja M Koshy, John V Heymach, Albert C Koong, Heath D Skinner.

BACKGROUND: Metformin reduces glucose uptake in physiologic tissues and has been shown to affect non-small cell lung cancer (NSCLC) metabolism. We hypothesized that positron emission tomography (PET) scans could detect the impact of metformin on glucose uptake in NSCLC and we sought to redundant test this hypothesis in a prospective clinical trial.
MATERIALS AND METHODS: A single-blinded phase II clinical trial was performed with subjects randomized 6:1 to 3 to 4 weeks of metformin versus placebo for inoperable early-stage NSCLC. PET scans were performed at baseline, mid-treatment (after 2 wk study medication), and 6 months postradiation. The primary endpoint of the trial was tumor metabolic response to metformin by PERCIST before definitive radiation. Stereotactic body radiotherapy to 50 Gy in 4 fractions was used for peripheral tumors and 70 Gy in 10 fractions for central tumors.
RESULTS: There were 14 subjects randomized to the metformin and 1 to placebo. Histologies were 60% adenocarcinoma, 33.3% squamous cell carcinoma, and 6.7% poorly differentiated carcinoma. At mid-treatment PET scan, 57% of subjects randomized to metformin met PERCIST criteria for metabolic response, of which 75% had progressive metabolic disease and 25% had partial metabolic response, whereas the placebo subject had stable metabolic disease. At 6 months, the metformin arm had 69% complete metabolic response, 23% partial metabolic response and 1 progressive metabolic disease, and the subject treated with placebo had a complete metabolic response. There were no CTCAE grade ≥3 toxicities.
CONCLUSIONS: Despite low accrual, majority of subjects treated with metformin had metabolic responses by PERCIST criteria on PET imaging. Contrary to the effect of metformin on most physiologic tissues, most tumors had increased metabolic activity in response to metformin.

DOI: https://doi.org/10.1097/COC.0000000000000632
Oncogene. 2020 Jan 28.

PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer.

Shailender S Chauhan, Rachel K Toth, Corbin C Jensen, Andrea L Casillas, David F Kashatus, Noel A Warfel.

Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small-cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live-cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intracellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC cells to chemotherapy and produced a synergistic antitumor response in vitro and in vivo. Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.

DOI: https://doi.org/10.1038/s41388-020-1168-9
Oncogene. 2020 Jan 27.

Overexpression of PSAT1 promotes metastasis of lung adenocarcinoma by suppressing the IRF1-IFNγ axis.

Yung-Chieh Chan, Yu-Chan Chang, Hsiang-Hao Chuang, Yi-Chieh Yang, Yuan-Feng Lin, Ming-Shyan Huang, Michael Hsiao, Chih-Jen Yang, Kuo-Tai Hua.

An increasing number of enzymes involved in serine biosynthesis have been identified and correlated with malignant evolution in various types of cancer. Here we showed that the overexpression of phosphoserine aminotransferase 1 (PSAT1) is widely found in lung cancer tissues compared with nontumor tissues and predicts a poorer prognosis in patients with lung adenocarcinoma. PSAT1 expression was examined in a tissue microarray by immunohistochemistry. The data show that the knockdown of PSAT1 dramatically inhibits the in vitro and in vivo metastatic potential of highly metastatic lung cancer cells; conversely, the enforced expression of exogenous PSAT1 predominantly enhances the metastatic potential of lung cancer cells. Importantly, manipulating PSAT1 expression regulates the in vivo tumor metastatic abilities in lung cancer cells. Adjusting the glucose and glutamine concentrations did not alter the PSAT1-driven cell invasion properties, indicating that this process might not rely on the activation of its enzymatic function. RNA microarray analysis of transcriptional profiling from PSAT1 alternation in CL1-5 and CL1-0 cells demonstrated that interferon regulatory factor 1 (IRF1) acts as a crucial regulator of PSAT1-induced gene expression upon metastatic progression. Decreasing the IRF1-IFIH1 axis compromised the PSAT1-prompted transcriptional reprogramming in cancer cells. Our results identify PSAT1 as a key regulator by a novel PSAT1/IRF1 axis in lung cancer progression, which may serve as a potential biomarker and therapeutic target for the treatment of lung cancer patients.

DOI: https://doi.org/10.1038/s41388-020-1160-4
J Biol Chem. 2020 Jan 30. pii: jbc.RA119.011930. [Epub ahead of print]

The GTPase KRAS suppresses the P53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells.

Hua Yang, Shengyan Xiang, Aslamuzzaman Kazi, Said M Sebti.

  In human cancer cells that harbor mutant KRAS and WT P53 (P53), KRAS contributes to the maintenance of low P53 levels. Moreover, KRAS depletion stabilizes and reactivates P53 and thereby inhibits malignant transformation. However, the mechanism by which KRAS regulates P53 is largely unknown. Recently, we showed that KRAS depletion leads to P53 Ser-15 phosphorylation (P-P53) and increases the levels of P53 and its target P21/wild-type P53-activated fragment 1 (WAF1)/CIP1. Here, using several human lung cancer cell lines, siRNA-mediated gene silencing, immunoblotting, quantitative RT-PCR, promoter-reporter assays and reactive oxygen species (ROS) assays, we demonstrate that KRAS maintains low P53 levels by activating the NFE2-related factor 2 (NRF2)-regulated antioxidant defense system. We found that KRAS depletion led to down-regulation of NRF2 and its targets NAD(P)H quinone dehydrogenase 1 (NQO1) and solute carrier family 7 member 11 (SLC7A11), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, and increased ROS levels. We noted that the increase in ROS is required for increased P-P53, P53, and P21/WAF1/CIP1 levels following KRAS depletion. Downstream of KRAS, depletion of RAS-like proto-oncogene B (RALB) and IκB kinase (IKK)-related TANK-binding kinase 1 (TBK1) activated P53 in a ROS- and NRF2-dependent manner. Consistent with this, the IKK inhibitor BAY11-7085 and dominant-negative mutant IκBαM inhibited NFκB activity and increased P-P53, P53, and P21/WAF1/CIP1 levels in a ROS-dependent manner. In conclusion, our findings uncover an important role for the NRF2-regulated antioxidant system in KRAS-mediated P53 suppression.

Keywords:  GTPase Kras (KRAS); Nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); RalB; TBK1; p53; reactive oxygen species (ROS); redox signaling

DOI:  https://doi.org/10.1074/jbc.RA119.011930
Oncogene. 2020 Jan 31.

AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics.

Miao Qi, Dan Dai, Jin Liu, Zhongqi Li, Panpan Liang, Yue Wang, Lu Cheng, Yihong Zhan, Zhifeng An, Yaoyao Song, Yana Yang, Xiaohui Yan, Hui Xiao, Huanjie Shao.

Mitochondrial fusion and fission dynamics fine-tune cellular calcium homeostasis, ATP production capacity and ROS production and play important roles in cell proliferation and migration. Dysregulated mitochondrial dynamics is closely related to tumor development, but the mechanism of mitochondrial dynamics dysregulation and its role in the development of lung cancer remains unclear. Here, we demonstrate that the DNA sensor protein absent in melanoma 2 (AIM2) is highly expressed in non-small cell lung cancer (NSCLC) cells and that high AIM2 expression is associated with poor prognosis in patients with NSCLC. High expression of AIM2 contributes to tumor cell growth and proliferation independent of inflammasome activation in vitro and in vivo. Further studies have shown that AIM2 colocalizes with mitochondria in NSCLC cells and that AIM2 knockdown leads to enhanced mitochondrial fusion and decreased cell proliferation. Mechanistic studies have shown that AIM2 downregulation promotes MFN2 upregulation, thereby enhancing mitochondrial fusion. Moreover, we found that mitochondrial fusion driven by AIM2 knockdown leads to a decrease of cellular reactive oxygen species (ROS) production, which further causes inactivation of the MAPK/ERK signaling pathway. Together, we discovered a novel function of AIM2 in promoting NSCLC development by regulating mitochondrial dynamics and revealed its underlying mechanism. Our work provides new intervention targets for the treatment of NSCLC.

DOI: https://doi.org/10.1038/s41388-020-1176-9
Clin Nutr ESPEN. 2020 Feb;pii: S2405-4577(19)30493-0. [Epub ahead of print]35 12-19

Accuracy of predictive equations versus indirect calorimetry for the evaluation of energy expenditure in cancer patients with solid tumors - An integrative systematic review study.

Rafaela Mazzo, Francieli Barreiro Ribeiro, Ana Carolina Junqueira Vasques.

   BACKGROUND & AIMS: Cancer is one the principal causes of death, and is considered a health issue worldwide. Cancer patients are at high risk of malnutrition due to the disease and the treatment itself. Nutritional therapy is part of a multi-modal treatment and it is important to be aware of the patient's energy expenditure to aid in decision-making for dietotherapeutic prescription. Indirect Calorimetry (IC) is the gold standard method for measuring energy expenditure (EE); but due to its often high cost in clinical practise, equations that measure energy expenditure are usually used.
OBJECTIVES: To perform an integrative systematic review, searching in the literature for how predictive equations of EE behave in relation to IC in cancer patients with solid tumors, considering the overall accuracy for cancer patients, the different tumor types, and the type of anti-cancer therapy applied.
METHODS: A review was carried out of systematic integrative type literature. The articles were searched for in three databases (Pubmed, Embase, and Web of Science) using descriptors accompanied by Boolean operators. Inclusion and exclusion criteria were determined, and the articles found went through selection, analysis and extraction of their results.
RESULTS: A total of 688 articles were identified that underwent a thorough selection, resulting in 15 studies that included in this review. In five studies, the results showed that predictive equations underestimated the EE of cancer patients; in three studies the EE was overestimated by predictive equations, and in seven studies predictive equations underestimated or overestimated the EE. The low accuracy of predictive EE equations was present regardless of tumor type and type of anti-cancer therapy received by patients.
CONCLUSION: The predictive energy expenditure equations available to date are generally not in accordance with IC results for cancer patients with solid tumors, since these individuals present clinical situations or are exposed to factors that alter EE and are not considered in these equations.

Keywords:  Cancer; Clinical practise; Indirect calorimetry; Predictive equations; Resting energy requirement

DOI:  https://doi.org/10.1016/j.clnesp.2019.11.001
Ann Thorac Cardiovasc Surg. 2020 Jan 29.

Preoperative Immune-Nutritional Abnormality Predicts Poor Outcome in Elderly Non-Small-Cell Lung Cancer Patients with Comorbidities.

Naoko Miura, Fumihiro Shoji, Yuka Kozuma, Gouji Toyokawa, Koji Yamazaki, Sadanori Takeo.

   BACKGROUND: Elderly non-small-cell lung cancer (NSCLC) patients are increasing. In general, elderly patients often have more comorbidities and worse immune-nutritional condition.
PATIENTS AND METHODS: In total, 122 NSCLC patients aged 75 years or older, underwent thoracic surgery between January 2007 and December 2010. In all, 99 of 122 patients (81.1%) who had preoperative comorbidities were retrospectively analyzed. We evaluated the preoperative immune-nutritional condition using the controlling nutritional status (CONUT) score.
RESULTS: We decided the best cutoff value for CONUT score was 1; as a result, 42 of 99 patients (42.4%) had abnormal preoperative CONUT score. Univariate analyses showed sex (P = 0.0099), smoking status (P = 0.0176), pathological stage (P = 0.0095), and preoperative CONUT score (P = 0.0175) significantly affected overall survival (OS). In multivariate analysis, pathological stage (relative risk (RR): 2.12; 95% confidence interval (CI): 1.10-3.90; P = 0.0268) and preoperative CONUT score (RR: 2.10; 95% CI: 1.20-3.67; P = 0.0094) were shown to be independent prognostic factors. In Kaplan-Meier analysis of OS, the preoperative abnormal CONUT score group had significantly shorter OS than did the preoperative normal CONUT score group (P = 0.0152, log-rank test); however, there were no statistical differences both in disease-free survival (DFS) and cancer-specific survival (CSS; P = 0.9238 and P = 0.8661, log-rank test, respectively). In total, 22 patients (46.8%) were dead caused by other diseases such as pneumonia or other organs malignancies.
CONCLUSION: Preoperative abnormal CONUT score is a poor prognostic factor for the elderly NSCLC patients with preoperative comorbidities and might predict poor postoperative outcome caused by not primary lung cancer but other diseases.

Keywords:  controlling nutritional status score; elderly patients; non-small-cell lung cancer; preoperative comorbidities; preoperative immune-nutritional status; surgical outcome

DOI:  https://doi.org/10.5761/atcs.oa.19-00207