bims-meluca 2019-05-19 papers

Nat Commun. 2019 May 14. 10(1): 2148

JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression.

Liu J, Wang T, Creighton CJ, Wu SP, Ray M, Janardhan KS, Willson CJ, Cho SN, Castro PD, Ittmann MM, Li JL, Davis RJ, DeMayo FJ.

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

DOI: https://doi.org/10.1038/s41467-019-09843-1

Cell Mol Biol (Noisy-le-grand). 2019 Apr 30. 65(4): 48-52

Ginsenoside compound K inhibits growth of lung cancer cells via HIF-1α-mediated glucose metabolism.

Chen HF, Wu LX, Li XF, Zhu YC, Wang WX, Xu CW, Huang ZZ, Du KQ.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. Compound K, an active metabolite of ginsenosides, is reported to exhibit anti-cancer property in various types of human malignancies. The present study investigated the role of compound K on glucose metabolism in NSCLC cells and its underlying mechanism. Our study found that compound K dose-dependently inhibited the cell viability of NSCLC cells. Moreover, administration with compound K decreased glucose uptake and lactate secretion under normoxic and hypoxic conditions. Consistently, the expression of key enzymes (HK II, PDK1 and LDHA) involved in glucose metabolism were inhibited in compound K-treated tumor cells. In addition, compound K inhibited the expression of HIF-1α and its downstream gene GLUT1. On the contrary, overexpression of HIF-1α elevated metabolic reactions and partly attenuated the inhibitory role of compound K on NSCLC cell growth. These results demonstrate that compound K suppresses NSCLC cell growth via HIF-1α mediated metabolic alteration, contributing to novel anticancer therapy by targeting glucose metabolism.

Keywords: Aerobic glycolysis.; Compound K; HIF-1α; Non-small cell lung cancer

Cancer Res. 2019 May 14. pii: canres.0182.2019. [Epub ahead of print]

Magnetic resonance imaging is more sensitive than PET for detecting treatment-induced cell death-dependent changes in glycolysis.

Hesketh RL, Wang J, Wright AJ, Lewis DY, Denton AE, Grenfell R, Miller JL, Bielik R, Gehrung M, Fala M, Ros S, Xie B, Hu DE, Brindle KM.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here we assess the abilities of positron emission tomography (PET) measurement of [18F]FDG uptake and magnetic resonance imaging (MRI) measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histological markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation was maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-0182

Expert Opin Emerg Drugs. 2019 May 16.

Emerging angiogenesis inhibitors for non-small cell lung cancer.

Malapelle U, Rossi A.

INTRODUCTION: Angiogenesis represent a complex process crucial during embryo development, wound healing, and collateral formation for improved organ perfusion. Numerous stimulatory and inhibitory pathways through their balance regulate angiogenesis and vascular homeostasis. Targeting the pathways implicated in the regulation of angiogenesis and neo-angiogenesis play an important role in cancers research, treatment and patients' outcome. Antiangiogenic strategies, including monoclonal antibodies binding vascular endothelial growth factor (VEGF) or the corresponding receptor and small molecules which inhibit the function of different angio-related tyrosine kinase, produced interesting results in cancer treatments including non-small-cell lung cancer (NSCLC). Areas covered: The current state-of-the-art of anti-angiogenesis treatment in the management of NSCLC patients is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken in order to discuss about emerging angiogenesis inhibitors in NSCLC. Expert opinion: Targeting angiogenesis remains an important therapeutic strategy in the management of NSCLC. Moreover, VEGF has been recognized having also an immunosuppressive activity leading to investigate the potential activity of angiogenic inhibitors in restoring the antitumor immunity by targeting VEGF/VEGF-Receptor. Furthermore, new anti-angiogenic drugs for which there is also the availability of predictive biomarkers are welcome.

Keywords: NSCLC; angiogenesis; monoclonal antibodies; small molecules; tyrosine kinase inhibitors

DOI: https://doi.org/10.1080/14728214.2019.1619696

Cancer Immunol Res. 2019 May 14. pii: canimm.0657.2018. [Epub ahead of print]

Targeting hypoxia-induced carbonic anhydrase IX enhances immune checkpoint blockade locally and systemically.

Chafe SC, McDonald PC, Saberi S, Nemirovsky O, Venkateswaran G, Burugu S, Gao D, Delaidelli A, Kyle AH, Baker JHE, Gillespie JA, Bashashati A, Minchinton AI, Zhou Y, Shah SP, Dedhar S.

Treatment strategies involving immune checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 melanoma patients. We found that targeting CAIX with the small molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with immune checkpoint blockade is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.

DOI: https://doi.org/10.1158/2326-6066.CIR-18-0657