bims-meluca 2020-03-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2020–03–01
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

Metabolic features of cancer cells in NRF2 addiction status.
An RNA-binding-protein, NONO governs energy metabolism by regulating NAMPT in lung cancer.
Alpha-lipoic acid inhibits lung cancer growth via mTOR-mediated autophagy inhibition.
TRIAP1 knockdown sensitizes non-small cell lung cancer to ionizing radiation by disrupting redox homeostasis.
Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation.
Potential Applications of NRF2 Modulators in Cancer Therapy.
Lung cancer aggressiveness in an intermittent hypoxia murine model of postmenopausal sleep apnea.

Biophys Rev. 2020 Feb 28.

Metabolic features of cancer cells in NRF2 addiction status.

Keito Okazaki, Thales Papagiannakopoulos, Hozumi Motohashi.

  The KEAP1-NRF2 system is a sulfur-employing defense mechanism against oxidative and electrophilic stress. NRF2 is a potent transcription activator for genes mediating sulfur-involving redox reactions, and KEAP1 controls the NRF2 activity in response to the stimuli by utilizing reactivity of sulfur atoms. In many human cancer cells, the KEAP1-mediated regulation of NRF2 activity is abrogated, resulting in the persistent activation of NRF2. Persistently activated NRF2 drives malignant progression of cancers by increasing therapeutic resistance and promoting aggressive tumorigenesis, a state termed as NRF2 addiction. In NRF2-addicted cancer cell, NRF2 contributes to metabolic reprogramming in cooperation with other oncogenic pathways. In particular, NRF2 strongly activates cystine uptake coupled with glutamate excretion and glutathione synthesis, which increases consumption of intracellular glutamate. Decreased availability of glutamate limits anaplerosis of the TCA cycle, resulting in low mitochondrial respiration, and nitrogen source, resulting in the high dependency on exogenous non-essential amino acids. The highly enhanced glutathione synthesis is also likely to alter sulfur metabolism, which can contribute to the maintenance of the mitochondrial membrane potential in normal cells. The potent antioxidant and detoxification capacity supported by abundant production of glutathione is achieved at the expense of central carbon metabolism and requires skewed metabolic flow of sulfur. These metabolic features of NRF2 addiction status provide clues for novel therapeutic strategies to target NRF2-addicted cancer cells.

Keywords:  Cysteine; Glutamate; Glutathione synthesis; KEAP1/NRF2; Metabolic liabilities; Non-essential amino acids; Sulfur metabolism

DOI:  https://doi.org/10.1007/s12551-020-00659-8
Biochem Biophys Res Commun. 2020 Feb 19. pii: S0006-291X(20)30028-0. [Epub ahead of print]

An RNA-binding-protein, NONO governs energy metabolism by regulating NAMPT in lung cancer.

Seong-Jin Kim, Jin-Sung Ju, Seok Soon Park, Young-Ah Suh, Hyun Ju Yoo, Eun Kyung Choi, Seong-Yun-Jeong, Yong Shin, Yun-Yong Park.

  The RNA binding proteins (RBPs) have multiple roles in human cancer. However, their molecular target and function have not been clearly identified. Our genomic analysis derived from patients reveals that NONO is a potential oncogenic gene in lung cancer. NONO is highly expressed in lung cancer tissues compared with normal tissues, and its expression has been correlated with the prognosis of lung cancer patients. We found that NONO significantly influences cancer cell proliferation in lung cancer. Gene expression profiles with NONO-depleted cells revealed that the sirtuin signaling pathway is highly correlated with NONO. Thus, NONO-silenced cells caused reduction of the TCA cycle and glycolysis metabolism. We identified that NONO regulated NAMPT, which is a well-known gene involved in sirtuin signaling, and NONO has a significant correlation with NAMPT in lung cancer patients. We propose that NONO modulates energy metabolism by direct interaction with NAMPT and suggest that a functional relationship between NONO and NAMPT contributes to lung cancer cell survival. Targeting the axis can be a promising approach for patient treatment in lung cancer.

Keywords:  Lung cancer; Metabolism; NONO; RBP

DOI:  https://doi.org/10.1016/j.bbrc.2020.01.011
FEBS Open Bio. 2020 Feb 23.

Alpha-lipoic acid inhibits lung cancer growth via mTOR-mediated autophagy inhibition.

Peipei Peng, Xiaojin Zhang, Tao Qi, Hao Cheng, Qiuyue Kong, Li Liu, Xiaofei Cao, Zhengnian Ding.

  Lung cancer is the leading cause of cancer-related death, and there remains a need for novel therapies for this malignancy. Here, we examined the effects of alpha-lipoic acid (LA), a drug used for treating human diabetic complications, on lung cancer growth. We report that LA limited lung cancer growth in xenograft mice and reduced lung cancer A549 cell viability. We observed autophagy activation in human lung cancers, and report that LA inactivated autophagy in A549 cells. In addition, LA activated mTOR/p70S6K signaling. Inhibition of mTOR with rapamycin reversed LA-induced inactivation of autophagy and abolished LA-induced suppression of A549 cell viability. Altogether, the data suggest that LA exerts an anti-lung cancer effect through mTOR-mediated inhibition of autophagy, and thus LA may have therapeutic potential for lung cancer management.

Keywords:  Alpha-lipoic acid (LA); Autophagy; Lung cancer; Mammalian target of rapamycin (mTOR); Rapamycin

DOI:  https://doi.org/10.1002/2211-5463.12820
Thorac Cancer. 2020 Feb 25.

TRIAP1 knockdown sensitizes non-small cell lung cancer to ionizing radiation by disrupting redox homeostasis.

Chun-Cheng Hao, Jia-Ning Luo, Cui-Yang Xu, Xin-Yu Zhao, Zhen-Bin Zhong, Xiao-Nan Hu, Xiao-Ming Jin, Xiaofeng Ge.

   BACKGROUND: Radioresistance of some non-small cell lung cancer (NSCLC) types increases the risk of recurrence or metastasis in afflicted patients, following radiotherapy. As such, further improvements to NSCLC radiotherapy are needed. The expression of oncogene TP53-regulated inhibitor of apoptosis 1 (TRIAP1) in NSCLC is increased following irradiation. Furthermore, gene set enrichment analysis (GSEA) has suggested that TRIAP1 might be involved in maintaining redox homeostasis. This in turn might enhance cell radioresistance.
METHODS: In this study we irradiated human NSCLC cell lines (A549 and H460), while knocking down TRIAP1, to determine whether a disrupted redox homeostasis could attenuate radioresistance.
RESULTS: Irradiation notably increased both mRNA and protein levels of TRIAP1. In addition, TRIAP1 knockdown decreased the expression of several antioxidant proteins, including thioredoxin-related transmembrane protein (TMX) 1, TMX2, thioredoxin (TXN), glutaredoxin (GLRX) 2, GLRX3, peroxiredoxin (PRDX) 3, PRDX4, and PRDX6 in A549 and H460 cells. In addition, silencing TRIAP1 impaired the radiation-induced increase of the aforementioned proteins. Continuing along this line, we observed a radiation-induced reduction of cell viability and invasion, as well as increased apoptosis and intracellular reactive oxygen species following TRIAP1 knockdown.
CONCLUSIONS: In summary, we identified TRIAP1 as a key contributor to the radioresistance of NSCLC by maintaining redox homeostasis.

Keywords:  Non-small cell lung cancer; TRIAP1; radioresistance; redox homeostasis

DOI:  https://doi.org/10.1111/1759-7714.13358
Clin Lung Cancer. 2020 Jan 27. pii: S1525-7304(20)30011-5. [Epub ahead of print]

Potential Benefits of Bevacizumab Combined With Platinum-Based Chemotherapy in Advanced Non-Small-Cell Lung Cancer Patients With EGFR Mutation.

Ichidai Tanaka, Masahiro Morise, Ayako Miyazawa, Yuta Kodama, Yutaro Tamiya, Soei Gen, Akira Matsui, Tetsunari Hase, Naozumi Hashimoto, Mitsuo Sato, Yoshinori Hasegawa.

   BACKGROUND: Oncogenic EGFR signaling has been shown to upregulate vascular endothelial growth factor A (VEGFA) expression involved in tumor angiogenesis. However, the clinical benefits of bevacizumab plus cytotoxic chemotherapy for EGFR mutation-positive patients remain unclear. This study aimed to investigate VEGFA messenger RNA expression in patients with EGFR mutation, and to further compare the efficacy of bevacizumab combined with platinum-based chemotherapy between EGFR-mutant and wild-type patients.
PATIENTS AND METHODS: Gene expression of various proangiogenic factors was analyzed in nonsquamous, non-small-cell lung cancer (NSCLC) patients using The Cancer Genome Atlas dataset. Additionally, clinical data of patients receiving carboplatin and pemetrexed (CPem; n = 104) or bevacizumab plus CPem (BevCPem; n = 55) at Nagoya University hospital were retrospectively assessed for progression-free survival and best overall response rate (ORR).
RESULTS: Among various proangiogenic factors, only VEGFA expression was significantly higher in patients with advanced nonsquamous NSCLC with EGFR mutation compared to wild-type patients (P = .0476). Progression-free survival in the BevCPem group was significantly longer in patients with EGFR mutation than in wild-type patients (10.5 vs. 6.6 months; Wilcoxon P = .0278), while the difference in the CPem group was not significant (6.6 vs. 4.5 months; Wilcoxon P = .1822). The ORRs in the BevCPem group were 54.5% and 36.4% for EGFR-mutant and wild-type patients, respectively, and the ORRs in the CPem group were 35.5% and 28.8 % in EGFR-mutant and wild-type patients, respectively.
CONCLUSION: VEGFA messenger RNA expression was significantly increased in advanced nonsquamous NSCLC harboring EGFR mutation, and BevCPem provided better clinical benefits to patients with EGFR mutation than wild-type carriers.

Keywords:  Carboplatin; Epidermal growth factor receptor; NSCLC; Pemetrexed; VEGFA

DOI:  https://doi.org/10.1016/j.cllc.2020.01.011
Antioxidants (Basel). 2020 Feb 25. pii: E193. [Epub ahead of print]9(3):

Potential Applications of NRF2 Modulators in Cancer Therapy.

Emiliano Panieri, Aleksandra Buha, Pelin Telkoparan-Akillilar, Dilek Cevik, Demetrios Kouretas, Aristidis Veskoukis, Zoi Skaperda, Aristidis Tsatsakis, David Wallace, Sibel Suzen, Luciano Saso.

  The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

Keywords:  NRF2-KEAP1; ROS; antioxidant; cancer metabolism; cancer therapy; chemoresistance; oxidative stress; radioresistance

DOI:  https://doi.org/10.3390/antiox9030193
Menopause. 2020 Feb 24.

Lung cancer aggressiveness in an intermittent hypoxia murine model of postmenopausal sleep apnea.

Marta Torres, Miguel Ángel Martinez-Garcia, Francisco Campos-Rodriguez, David Gozal, Josep M Montserrat, Daniel Navajas, Ramon Farré, Isaac Almendros.

OBJECTIVE: Intermittent hypoxia (IH)-a hallmark of obstructive sleep apnea (OSA)-enhances lung cancer progression in mice via altered host immune responses that are also age and sex-dependent. However, the interactions of menopause with IH on tumor malignant properties remain unexplored. Here, we aimed to investigate lung cancer outcomes in the context of ovariectomy (OVX)-induced menopause in a murine model of OSA.
METHODS: Thirty-four female mice (C57BL/6, 12-week-old) were subjected to bilateral OVX or to Sham intervention. Six months after surgery, mice were pre-exposed to either IH or room air (RA) for 2 weeks. Then, 10 lung carcinoma (LLC1) cells were injected subcutaneously in the left flank, with IH or RA exposures continued for 4 weeks. Tumor weight, tumor invasion, and spontaneous lung metastases were assessed. Tumor-associated macrophages (TAMs) were isolated and subjected to flow cytometry polarity evaluation along with assessment of TAMs modulation of LLC1 proliferation in vitro. To determine the effect of IH and OVX on each experimental variable, a two-way analysis of variance was performed.
RESULTS: IH and OVX promoted a similar increase in tumor growth (∼2-fold; P = 0.05 and ∼1.74-fold; P < 0.05, respectively), and OVX-IH further increased it. Regarding lung metastasis, the concurrence of OVX in mice exposed to IH enhanced the number of metastases (23.7 ± 8.0) in comparison to those without OVX (7.9 ± 2.8; P < 0.05). The pro-tumoral phenotype of TAMS, assessed as M2/M1 ratio, was increased in OVX (0.06 ± 0.01; P < 0.01) and IH (0.06 ± 0.01; P < 0.01) compared with sham/RA conditions (0.14 ± 0.03). The co-culture of TAMS with naive LLC1 cells enhanced their proliferation only under IH.
CONCLUSION: In female mice, both the IH that is characteristically present in OSA and OVX as a menopause model emerge as independent contributors that promote lung cancer aggressiveness and seemingly operate through alterations in the host immune response.

DOI: https://doi.org/10.1097/GME.0000000000001526