bims-meluca 2019-01-06 papers

Cancers (Basel). 2019 Jan 02. pii: E37. [Epub ahead of print]11(1):

Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer.

Hodakoski C, Hopkins BD, Zhang G, Su T, Cheng Z, Morris R, Rhee KY, Goncalves MD, Cantley LC.

Cancer cells can adapt to nutrient poor conditions by rewiring their metabolism and using alternate fuel sources. Identifying these adaptive metabolic pathways may provide novel targets for cancer therapy. Here, we identify a subset of non-small cell lung cancer (NSCLC) cell lines that survive in the absence of glucose by internalizing and metabolizing extracellular protein via macropinocytosis. Macropinocytosis is increased in these glucose independent cells, and is regulated by phosphoinositide 3-kinase (PI3K) activation of Rac-Pak signaling. Furthermore, inhibition of Rac-dependent macropinocytosis blocks glucose-independent proliferation. We find that degradation of internalized protein produces amino acids, including alanine, which generates TCA cycle and glycolytic intermediates in the absence of glucose. In this process, the conversion of alanine to pyruvate by alanine transaminase 2 (ALT2) is critical for survival during glucose starvation. Collectively, Rac driven macropinocytosis of extracellular protein is an adaptive metabolic pathway used by a subset of lung cancers to survive states of glucose deprivation, and may serve as a potential drug target for cancer therapy.

Keywords: Rac; glucose; macropinocytosis; metabolism

DOI: https://doi.org/10.3390/cancers11010037

Eur J Med Chem. 2018 Dec 24. pii: S0223-5234(18)31094-8. [Epub ahead of print]164 252-262

High-throughput screening of novel pyruvate dehydrogenase kinases inhibitors and biological evaluation of their in vitro and in vivo antiproliferative activity.

Wu DM, Wang YJ, Fan SH, Zhang ZF, Shan Q, Lu J, Chen GQ, Zheng YL.

Overexpression of pyruvate dehydrogenase kinases (PDKs) has been widely noticed in a variety of human solid tumors, which could be regarded as an attractive therapeutic target for cancer therapy. In this paper, we present an enzymatic screening assay and multiple biological evaluations for the identification of potential PDKs, especially PDK1 inhibitors. We identified 9 potential PDKs inhibitors from the screening of an in-house small molecule library, all of the identified inhibitors reduced pyruvate dehydrogenase (PDH) complex phosphorylation. Among which, 4, 5, and 9 displayed the most potent PDKs inhibitory activities, with EC50 values of 0.34, 1.4, and 1.6 μM in an enzymatic assay, respectively. A kinase inhibition assay suggested that 4, 5, and 9 were pan-isoform PDK inhibitors, but more sensitive to PDK1. Meanwhile, the three compounds inhibited HSP90, with IC50 values of 0.78, 3.58, and 2.70 μM, respectively. The cell viability assay indicated that 4 inhibited all of the tested cancer cells proliferation, with a GC50 value of 2.3 μM against NCIH1975 cell, but has little effect on human normal lung cell BEAS-2B cell. In the NCIH1975 xenograft models, 4 displayed strong antitumor activities at a dose of 10 and 20 mg/kg, but with no negative effect on the mice weight. In addition, 4 decreased the ECAR and lactate formation, increased OCR and ROS level in NCIH1975 cancer cell, which could be used as a promising modulator to reprogram the glucose metabolic pathways in NCIH1975 cancer cells.

Keywords: Anticancer drug; Cancer metabolism; Kinase inhibition; Pyruvate dehydrogenase kinase

DOI: https://doi.org/10.1016/j.ejmech.2018.12.051

Cancer Res. 2019 Jan 04. pii: canres.2545.2018. [Epub ahead of print]

Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis.

Jeong H, Kim S, Hong BJ, Lee CJ, Kim YE, Bok S, Oh JM, Gwak SH, Yoo MY, Lee MS, Chung SJ, Defrêne J, Tessier P, Pelletier M, Jeon H, Roh TY, Kim B, Kim KH, Ju JH, Kim S, Lee YJ, Kim DW, Kim IH, Kim HJ, Park JW, Lee YS, Lee JS, Cheon GJ, Weissman IL, Chung DH, Jeon YK, Ahn GO.

Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in non-small cell lung cancer (NSCLC) patients. We found a strong correlation between CD68 TAM immunostaining and positron emission tomography (PET) 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of NSCLC patients. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 NSCLC patients from the TCGA database. TAM secreted tumor necrosis factor-α (TNF-α) to promote tumor cell glycolysis while increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies including immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-18-2545