bims-meluca 2022-02-13 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2022–02–13
ten 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

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.
Serum IL-35 levels is a new candidate biomarker of cancer-related cachexia in stage IV non-small cell lung cancer.
USP47 stabilizes BACH1 to promote the Warburg effect and non-small cell lung cancer development via stimulating Hk2 and Gapdh transcription.
Aldolase A and Phospholipase D1 Synergistically Resist Alkylating Agents and Radiation in Lung Cancer.
Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.
CEBPB is Required for NRF2-Mediated Drug Resistance in NRF2-Activated Non-Small Cell Lung Cancer Cells.
Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer.
Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism.
Systemic Analyses of the Expression of TPI1 and Its Associations with Tumor Microenvironment in Lung Adenocarcinoma and Squamous Cell Carcinoma.
Escape From Cisplatin-Induced Senescence of Hypoxic Lung Cancer Cells Can Be Overcome by Hydroxychloroquine.

Nat Metab. 2022 Feb 10.

Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.

Jiang-Sha Zhao, Shuo Shi, Hai-Yan Qu, Zuzana Keckesova, Zi-Jian Cao, Li-Xian Yang, Xiaofu Yu, Limin Feng, Zhong Shi, Joanna Krakowiak, Ruo-Ying Mao, Yi-Tong Shen, Yu-Meng Fan, Tian-Min Fu, Cunqi Ye, Daqian Xu, Xiaofei Gao, Jia You, Wenbo Li, Tingbo Liang, Zhimin Lu, Yu-Xiong Feng.

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

DOI: https://doi.org/10.1038/s42255-021-00524-2
Thorac Cancer. 2022 Feb 09.

Serum IL-35 levels is a new candidate biomarker of cancer-related cachexia in stage IV non-small cell lung cancer.

Zengxun Li, Lei Zhu, Han Zheng, Wenna Jiang, Yifei Wang, Zhansheng Jiang, Jie Xu.

   BACKGROUND: Cancer-related cachexia is a major cause of treatment resistance and poor prognosis, which is characterized by anorexia and skeletal muscle depletion. To date, there have been no reports on the relationship between IL-35 and cancer-related cachexia in patients with stage IV non-small cell lung cancer.
METHODS: Serum IL-35 levels in 86 patients with stage IV NSCLC were measured and statistically analyzed based on patients' clinicopathological parameters. Serum albumin levels, C-reactive protein, and skeletal muscle index (SMI) of the patients were also determined. In vivo studies using a mouse model were also conducted by subcutaneously injecting immunodeficiency (SCID) mice with overexpressing IL-35 cell lines and determining their daily food intake, bodyweight and muscle atrophy. Cachexia indicators were measured again after administering the mice with an anti-IL35 neutralizing antibody.
RESULTS: Patients with stage IV NSCLC had significantly higher serum IL-35 levels than the healthy controls. Similarly, circulating IL-35 levels were significantly higher in patients with cachexia than those without. The SMI values of patients with high serum IL-35 levels were significantly lower than those with low serum IL-35 levels. Mice subcutaneously injected with LLC PLV-IL-35 cell lines exhibited anorexia, weight loss, and muscle atrophy. Moreover, these symptoms were significantly reduced after administering the mice with an anti-IL35 neutralizing antibody.
CONCLUSIONS: This study reveals that high serum IL-35 expression is associated with non-small cell lung cancer cachexia and skeletal muscle atrophy. These findings highlight its potential as a biomarker and therapeutic target for controlling cachexia of advanced lung cancer.

Keywords:  IL-35; SMI; cachexia; skeletal muscle atrophy; stage IV NSCLC

DOI:  https://doi.org/10.1111/1759-7714.14307
Am J Cancer Res. 2022 ;12(1): 91-107

USP47 stabilizes BACH1 to promote the Warburg effect and non-small cell lung cancer development via stimulating Hk2 and Gapdh transcription.

Jing Peng, Wencan Li, Nianxi Tan, Xihua Lai, Weilin Jiang, Guang Chen.

Increasing studies demonstrated that ubiquitination plays a crucial part in the pathogenesis of non-small cell lung cancer (NSCLC), and targeted adjustment of the deubiquitination enzymes is a potential means for cancer treatment. However, the role of ubiquitin carboxyl-terminal hydrolase 47 (USP47) in NSCLC is still unclear. Here, we show that USP47 was upregulated in NSCLC clinical tissues and greatly related to advanced tumor stages and survival rate. Functional experimental results showed that USP47 promoted the cell proliferation in vitro and tumor growth in vivo. And the overexpression of USP47 promoted the glycolysis capacity of lung cancer cells. Mechanistic investigations showed that USP47 promoted NSCLC development, which depends a lot on directly binding to and deubiquitination of the basic leucine zipper transcription factor 1 (BACH1, BTB and CNC homology 1). BACH1 was also significantly overexpressed in primary NSCLC tissues and positively correlated with the expression of USP47. The promotion of USP47 on the Warburg effect and NSCLC progression was mediated by the deubiquitination of BACH1 and the downstream transcriptional regulation of hexokinase 2 (Hk2) and glyceraldehyde-phosphate dehydrogenase (Gapdh). Therefore, targeting USP47/BACH1 axis might offer a new way to inhibit the progression of NSCLC.

Keywords: BACH1; Non-small cell lung cancer; USP47; Warburg effect; deubiquitination
Front Oncol. 2021 ;11 811635

Aldolase A and Phospholipase D1 Synergistically Resist Alkylating Agents and Radiation in Lung Cancer.

Yu-Chan Chang, Peter Mu-Hsin Chang, Chien-Hsiu Li, Ming-Hsien Chan, Yi-Jang Lee, Ming-Huang Chen, Michael Hsiao.

  Exposure to alkylating agents and radiation may cause damage and apoptosis in cancer cells. Meanwhile, this exposure involves resistance and leads to metabolic reprogramming to benefit cancer cells. At present, the detailed mechanism is still unclear. Based on the profiles of several transcriptomes, we found that the activity of phospholipase D (PLD) and the production of specific metabolites are related to these events. Comparing several particular inhibitors, we determined that phospholipase D1 (PLD1) plays a dominant role over other PLD members. Using the existing metabolomics platform, we demonstrated that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) are the most critical metabolites, and are highly dependent on aldolase A (ALDOA). We further demonstrated that ALDOA could modulate total PLD enzyme activity and phosphatidic acid products. Particularly after exposure to alkylating agents and radiation, the proliferation of lung cancer cells, autophagy, and DNA repair capabilities are enhanced. The above phenotypes are closely related to the performance of the ALDOA/PLD1 axis. Moreover, we found that ALDOA inhibited PLD2 activity and enzyme function through direct protein-protein interaction (PPI) with PLD2 to enhance PLD1 and additional carcinogenic features. Most importantly, the combination of ALDOA and PLD1 can be used as an independent prognostic factor and is correlated with several clinical parameters in lung cancer. These findings indicate that, based on the PPI status between ALDOA and PLD2, a combination of radiation and/or alkylating agents with regulating ALDOA-PLD1 may be considered as a new lung cancer treatment option.

Keywords:  ALDOA; PLD; alkylating agents; lung cancer; radiation

DOI:  https://doi.org/10.3389/fonc.2021.811635
Front Oncol. 2021 ;11 794735

Deferoxamine Counteracts Cisplatin Resistance in A549 Lung Adenocarcinoma Cells by Increasing Vulnerability to Glutamine Deprivation-Induced Cell Death.

Wen-Jun Liu, Peng-Yu Pan, Ye Sun, Jian-Bo Wang, Huan Zhou, Xin Xie, Zhi-Yuan Duan, Han-Yu Dong, Wen-Na Chen, Li-de Zhang, Chun Wang.

  Glutamine, like glucose, is a major nutrient consumed by cancer cells, yet these cells undergo glutamine starvation in the cores of tumors, forcing them to evolve adaptive metabolic responses. Pharmacologically targeting glutamine metabolism or withdrawal has been exploited for therapeutic purposes, but does not always induce cancer cell death. The mechanism by which cancer cells adapt to resist glutamine starvation in cisplatin-resistant non-small-cell lung cancer (NSCLC) also remains uncertain. Here, we report the potential metabolic vulnerabilities of A549/DDP (drug-resistant human lung adenocarcinoma cell lines) cells, which were more easily killed by the iron chelator deferoxamine (DFO) during glutamine deprivation than their parental cisplatin-sensitive A549 cells. We demonstrate that phenotype resistance to cisplatin is accompanied by adaptive responses during glutamine deprivation partly via higher levels of autophagic activity and apoptosis resistance characteristics. Moreover, this adaptation could be explained by sustained glucose instead of glutamine-dominant complex II-dependent oxidative phosphorylation (OXPHOS). Further investigation revealed that cisplatin-resistant cells sustain OXPHOS partly via iron metabolism reprogramming during glutamine deprivation. This reprogramming might be responsible for mitochondrial iron-sulfur [Fe-S] cluster biogenesis, which has become an "Achilles' heel," rendering cancer cells vulnerable to DFO-induced autophagic cell death and apoptosis through c-Jun N-terminal kinase (JNK) signaling. Finally, in vivo studies using xenograft mouse models also confirmed the growth-slowing effect of DFO. In summary, we have elucidated the adaptive responses of cisplatin-resistant NSCLC cells, which balanced stability and plasticity to overcome metabolic reprogramming and permitted them to survive under stress induced by chemotherapy or glutamine starvation. In addition, for the first time, we show that suppressing the growth of cisplatin-resistant NSCLC cells via iron chelator-induced autophagic cell death and apoptosis was possible with DFO treatment. These findings provide a solid basis for targeting mitochondria iron metabolism in cisplatin-resistant NSCLC for therapeutic purposes, and it is plausible to consider that DFO facilitates in the improvement of treatment responses in cisplatin-resistant NSCLC patients.

Keywords:  NSCLC; cell death; cisplatin resistance; deferoxamine; glutamine deprivation; metabolic reprogramming

DOI:  https://doi.org/10.3389/fonc.2021.794735
J Biochem. 2022 Feb 07. pii: mvac013. [Epub ahead of print]

CEBPB is Required for NRF2-Mediated Drug Resistance in NRF2-Activated Non-Small Cell Lung Cancer Cells.

Keito Okazaki, Hayato Anzawa, Fumiki Katsuoka, Kengo Kinoshita, Hiroki Sekine, Hozumi Motohashi.

  NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. While increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CEBPB cooperates with NRF2 in NRF2-activated lung cancer and enhances tumor-initiating activity by promoting NOTCH3 expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB-coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.

Keywords:  CEBPB; NRF2; drug metabolism; enhancer; non-small cell lung cancer

DOI:  https://doi.org/10.1093/jb/mvac013
Cell Death Dis. 2022 Feb 08. 13(2): 129

Exosome-mediated miR-7-5p delivery enhances the anticancer effect of Everolimus via blocking MNK/eIF4E axis in non-small cell lung cancer.

Sile Liu, Weiyuan Wang, Yue Ning, Hongmei Zheng, Yuting Zhan, Haihua Wang, Yang Yang, Jiadi Luo, Qiuyuan Wen, Hongjing Zang, Jinwu Peng, Jian Ma, Songqing Fan.

Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.

DOI: https://doi.org/10.1038/s41419-022-04565-7
Cancer Sci. 2022 Feb 12.

Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism.

Jiayi Gu, Yingxue Qi, Yuxin Lu, Qianying Tao, Die Yu, Chunchun Jiang, Jianwen Liu, Xin Liang.

  Tumor metastasis is a series of complicated biological events. Hematogenous metastasis mediated by von Willebrand factor (vWF) is critical in tumor metastasis. However, the source of vWF and its role in tumor metastasis are controversial, and the further mechanism involved in mediating tumor metastasis is still unclear. In this study, we first demonstrated that lung adenocarcinoma cells could express vWF de novo and promotes tumor metastasis. Through the analysis of transcriptome sequencing, metastasis promotion effect of vWF may be related to phosphorylase kinase subunit G1 (PHKG1), a catalytic subtype of phosphorylase kinase PhK. PHKG1 was highly expressed in lung adenocarcinoma patients and led to poor prognosis. Further experiments found that lung adenocarcinoma-derived vWF induced the up-regulation of PHKG1 through the PI3K/AKT pathway to promote glycogenolysis. Glycogen was funneled into glycolysis, leading to increased metastasis. Tumor metastasis assayed in vitro and in vivo showed that knockdown of PHKG1 or synergistic injection of phosphorylase inhibition based on the overexpression of vWF could inhibit metastasis. In summary, our research proved that lung adenocarcinoma-derived vWF may mediate tumor metastasis by regulating PHKG1 to promote glycogen metabolism, and suggested potential targets for inhibition of lung adenocarcinoma metastasis.

Keywords:  PHKG1; glycogen; metabolism; tumor metastasis; vWF

DOI:  https://doi.org/10.1111/cas.15298
Dis Markers. 2022 ;2022 6258268

Systemic Analyses of the Expression of TPI1 and Its Associations with Tumor Microenvironment in Lung Adenocarcinoma and Squamous Cell Carcinoma.

Xiaodong Yang, Cong Ye, Hui Zheng, Chenyang Dai, Yuming Zhu.

Background: Recent studies have shown that the expression level of triosephosphate isomerase 1 (TPI1) may be associated with the occurrence and metastasis of tumors, but the expression level of TPI1 and its effect on lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are not yet clear.
Methods: We comprehensively explored and validated the TPI1 expression in lung adenocarcinoma and lung squamous cell carcinoma in public datasets. The associations of TPI1 expression with clinicopathological characteristics and prognosis were also studied in both histological types. Moreover, we analyzed the potential relations of TPI1 with immunomodulators and immune cell infiltrations in the tumor microenvironment based on previous literatures and bioinformatic tools.
Results: We found that TPI1 was significantly overexpressed in LUAD and LUSC. Significant associations of TPI1 expression were observed regarding age, gender, and pathological stages in LUAD. However, similar trend was only found with respect to age in LUSC. The high expression of TPI1 was significantly associated with worse survival in LUAD, but not in LUSC. Furthermore, we explored the potential distribution and changes of TPI1 expression in tumor microenvironment. Pathway enrichment analyses were performed to identify possible roles of TPI1 in both lung cancers.
Conclusions: TPI1 was overexpressed in both LUAD and LUSC. Increased TPI1 expression was correlated with poor prognosis in LUAD and changed immune cell infiltrating in various degrees in both histological types. Our study provides insights in understanding the potential roles of TPI1 in tumor progression and immune microenvironment.

DOI: https://doi.org/10.1155/2022/6258268
Front Oncol. 2021 ;11 738385

Escape From Cisplatin-Induced Senescence of Hypoxic Lung Cancer Cells Can Be Overcome by Hydroxychloroquine.

Aleksandra Olszewska, Agata Borkowska, Monika Granica, Justyna Karolczak, Bartosz Zglinicki, Claudine Kieda, Halina Was.

  Chemotherapy is the commonly used treatment for advanced lung cancer. However, it produces side effects such as the development of chemoresistance. A possible responsible mechanism may be therapy-induced senescence (TIS). TIS cells display increased senescence-associated β-galactosidase (SA-β-gal) activity and irreversible growth arrest. However, recent data suggest that TIS cells can reactivate their proliferative potential and lead to cancer recurrence. Our previous study indicated that reactivation of proliferation by TIS cells might be related with autophagy modulation. However, exact relationship between both processes required further studies. Therefore, the aim of our study was to investigate the role of autophagy in the senescence-related chemoresistance of lung cancer cells. For this purpose, human and murine lung cancer cells were treated with two commonly used chemotherapeutics: cisplatin (CIS), which forms DNA adducts or docetaxel (DOC), a microtubule poison. Hypoxia, often overlooked in experimental settings, has been implicated as a mechanism responsible for a significant change in the response to treatment. Thus, cells were cultured under normoxic (~19% O2) or hypoxic (1% O2) conditions. Herein, we show that hypoxia increases resistance to CIS. Lung cancer cells cultured under hypoxic conditions escaped from CIS-induced senescence, displayed reduced SA-β-gal activity and a decreased percentage of cells in the G2/M phase of the cell cycle. In turn, hypoxia increased the proliferation of lung cancer cells and the proportion of cells proceeding to the G0/G1 phase. Further molecular analyses demonstrated that hypoxia inhibited the prosenescent p53/p21 signaling pathway and induced epithelial to mesenchymal transition in CIS-treated cancer cells. In cells treated with DOC, such effects were not observed. Of importance, pharmacological autophagy inhibitor, hydroxychloroquine (HCQ) was capable of overcoming short-term CIS-induced resistance of lung cancer cells in hypoxic conditions. Altogether, our data demonstrated that hypoxia favors cancer cell escape from CIS-induced senescence, what could be overcome by inhibition of autophagy with HCQ. Therefore, we propose that HCQ might be used to interfere with the ability of senescent cancer cells to repopulate following exposure to DNA-damaging agents. This effect, however, needs to be tested in a long-term perspective for preclinical and clinical applications.

Keywords:  autophagy; cancer; chemoresistance; hypoxia; senescence

DOI:  https://doi.org/10.3389/fonc.2021.738385