bims-meluca 2021-09-26 papers

Cancer Metab. 2021 Sep 23. 9(1): 33

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.

Kasey R Cargill, C Allison Stewart, Elizabeth M Park, Kavya Ramkumar, Carl M Gay, Robert J Cardnell, Qi Wang, Lixia Diao, Li Shen, You-Hong Fan, Wai Kin Chan, Philip L Lorenzi, Trudy G Oliver, Jing Wang, Lauren A Byers.

INTRODUCTION: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.METHODS: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.
RESULTS: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.
CONCLUSIONS: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

Keywords: Glycolysis; MYC; Metabolism; PFK158; Small cell lung cancer

DOI: https://doi.org/10.1186/s40170-021-00270-9

Mol Cancer Ther. 2021 Sep 22. pii: molcanther.0033.2021. [Epub ahead of print]

Heme sequestration as an effective strategy for the suppression of tumor growth and progression.

Tianyuan Wang, Adnin Ashrafi, Purna Chaitanya Konduri, Poorva Ghosh, Sanchareeka Dey, Parsa Modareszadeh, Narges Salamat, Parinaz Sadat Alemi, Eranda Berisha, Li Zhang.

Heme is an essential nutritional, metabolic, and signaling molecule in living organisms. Pathogenic microbes extract heme from hosts to obtain metallonutrient, while heme fuels mitochondrial respiration and ATP generation in lung tumor cells. Here, we generated small heme-sequestering proteins (HeSPs) based on bacterial hemophores. These HeSPs contain neutral mutations in the heme-binding pocket and hybrid sequences from hemophores of different bacteria. We showed that HeSPs bound to heme and effectively extracted heme from hemoglobin. They strongly inhibited heme uptake and cell proliferation and induced apoptosis in non-small lung cancer (NSCLC) cells, while their effects on non-tumorigenic cell lines representing normal lung cells were not significant. HeSPs strongly suppressed the growth of human NSCLC tumor xenografts in mice. HeSPs decreased oxygen consumption rates and ATP levels in tumor cells isolated from treated mice, while they did not affect liver and blood cell functions. Immunohistochemistry, along with data from Western blotting and functional assays, revealed that HeSPs reduced the levels of key proteins involved in heme uptake, as well as the consumption of major fuels for tumor cells, glucose and glutamine. Further, we found that HeSPs reduced the levels of angiogenic and vascular markers, as well as vessel density in tumor tissues. Together, these results demonstrate that HeSPs act via multiple mechanisms, including the inhibition of oxidative phosphorylation, to suppress tumor growth and progression. Evidently, heme sequestration can be a powerful strategy for suppressing lung tumors and likely drug-resistant tumors that rely on oxidative phosphorylation for survival.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0033

Mol Ther Oncolytics. 2021 Sep 24. 22 368-379

miR-519d-3p suppresses tumorigenicity and metastasis by inhibiting Bcl-w and HIF-1α in NSCLC.

Jae Yeon Choi, Hyun Jeong Seok, Rae-Kwon Kim, Mi Young Choi, Su-Jae Lee, In Hwa Bae.

Bcl-w, a member of the Bcl-2 family, is highly expressed in various solid tumor, including lung cancer, suggesting that it is involved in cancer cell survival and carcinogenesis. Solid cancer-induced hypoxia has been reported to increase angiogenesis, growth factor, gene instability, invasion, and metastasis. Despite many studies on the treatment of non-small cell lung cancer (NSCLC) with a high incidence rate, the survival rate of patients has not improved because the cancer cells acquired resistance to treatment. This study investigated the correlation between Bcl-w expression and hypoxia in tumor malignancy of NSCLC. Meanwhile, microRNAs (miRNAs) are involved in a variety of key signaling mechanisms associated with hypoxia. Therefore, we discovered miR-519d-3p, which inhibits the expression of Bcl-w and hypoxia-inducing factor (HIF)-1α, and found that it reduces hypoxia-induced tumorigenesis. Spearman's correlation analysis showed that the expression levels of miR-519d-3p and Bcl-w/HIF-1α were negatively correlated, respectively. This showed that miR-519d-3p can be used as a diagnostic biomarker and target therapy for NSCLC.

Keywords: Bcl-w; HIF-1α; NSCLC; hypoxia; miR-519d-3p; solid tumor

DOI: https://doi.org/10.1016/j.omto.2021.06.015

Cell Metab. 2021 Sep 17. pii: S1550-4131(21)00421-6. [Epub ahead of print]

Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

Samantha M Morrissey, Fan Zhang, Chuanlin Ding, Diego Elias Montoya-Durango, Xiaoling Hu, Chenghui Yang, Zhen Wang, Fang Yuan, Matthew Fox, Huang-Ge Zhang, Haixun Guo, David Tieri, Maiying Kong, Corey T Watson, Robert A Mitchell, Xiang Zhang, Kelly M McMasters, Jian Huang, Jun Yan.

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.

Keywords: NF-kB; PD-L1; exosomes; glycolysis; immunosuppression; lactate; metastasis

DOI: https://doi.org/10.1016/j.cmet.2021.09.002