bims-meluca 2020-02-16 papers

Cell Rep. 2020 Feb 11. pii: S2211-1247(20)30052-8. [Epub ahead of print]30(6): 1780-1797.e6

Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway.

Wang C, Zhang S, Liu J, Tian Y, Ma B, Xu S, Fu Y, Luo Y.

Cancer cell-derived secretomes have been documented to play critical roles in cancer progression. Intriguingly, alternative extracellular roles of intracellular proteins are involved in various steps of tumor progression, which can offer strategies to fight cancer. Herein, we identify lung cancer progression-associated secretome signatures using mass spectrometry analysis. Among them, PKM2 is verified to be highly expressed and secreted in lung cancer cells and clinical samples. Functional analyses demonstrates that secreted PKM2 facilitates tumor metastasis. Furthermore, mass spectrometry analysis and functional validation identify integrin β1 as a receptor of secreted PKM2. Mechanistically, secreted PKM2 directly bound to integrin β1 and subsequently activated the FAK/SRC/ERK axis to promote tumor metastasis. Collectively, our findings suggest that PKM2 is a potential serum biomarker for diagnosing lung cancer and that targeting the secreted PKM2-integrin β1 axis can inhibit lung cancer development, which provides evidence of a potential therapeutic strategy in lung cancer.

Keywords: PKM2; integrin β1; lung cancer; metastasis; secretome

DOI: https://doi.org/10.1016/j.celrep.2020.01.037

J Cancer. 2020 ;11(6): 1403-1411

The Molecular Mechanism of Metabolic Remodeling in Lung Cancer.

Chang L, Fang S, Gu W.

Metabolic remodeling is a key phenomenon in the occurrence and development of tumors. It not only offers materials and energy for the survival and proliferation of tumor cells, but also protects tumor cells so that they may survive, proliferate and transfer in the harsh microenvironment. This paper attempts to reveal the role of abnormal metabolism in the development of lung cancer by considering the processes of glycolysis and lipid metabolism, Identification of the molecules that are specifically used in the processes of glycolysis and lipid metabolism, and their underlying molecular mechanisms, is of great clinical and theoretical significance. We will focus on the recent progress in elucidating the molecular mechanism of metabolic remodeling in lung cancer.

Keywords: Glycolysis; Lipid metabolism; Lung cancer; Molecular mechanism

DOI: https://doi.org/10.7150/jca.31406

BMC Pulm Med. 2020 Feb 13. 20(1): 40

CHCHD2 is a potential prognostic factor for NSCLC and is associated with HIF-1a expression.

Yin X, Xia J, Sun Y, Zhang Z.

BACKGROUND: CHCHD2 was identified a novel cell migration-promoting gene, which could promote cell migration and altered cell adhesion when ectopically overexpressed in NIH3T3 fibroblasts, and it was identified as a protein necessary for OxPhos function as well. However, the clinic relevance of CHCHD2 expression in NSCLC remains unclear. Here we assumed that CHCHD2 expression would accompanies the expression of HIF-1α to response hypoxia in the occurrence of NSCLC.METHODS: In order to verify this hypothesis, correlations among the expression levels of CHCHD2 and HIF-1α were detected and analyzed in 209 pair cases of NSCLC. The expression and location of these molecules were assessed using Immunohistochemistry, immunohistofluorescence, qRT-PCR and western blotting. The differences and correlations of the expression of these two molecules with clinical pathological characteristics in NSCLC were statistically analyzed using Wilcoxon (W) text, Mann-Whitney U, Kruskal-Wallis H and cross-table tests. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of the expression of CHCHD2 and HIF-1α on the patients' survival.
RESULTS: Data showed that CHCHD2 and HIF-1α expression were higher in NSCLC than in normal tissues (all P = 0.000). CHCHD2 expression was significantly related with smoking, tumor size, differentiation degree, TNM Stage, lymph metastasis (all P<0.05). The HIF-1α expression was significantly associated with smoking, tumor category, differentiation degree, TNM Stage, Lymph metastasis (all P<0.05). There was a marked correlation of CHCHD2 and HIF-1α expression with histological type, differentiation and lymph metastasis of NSCLC (all P<0.05, rs>0.3). Immunohistofluorescence showed that there were co-localization phenomenon in cytoplasm and nucleus between CHCHD2 and HIF-1α expression. NSCLC patients with higher CHCHD2 and HIF-1α expression had a significantly worse prognosis than those with lower CHCHD2 and HIF-1α expression (all P = 0.0001; log-rank test). The multivariate analysis indicated that CHCHD2 expression was an independent prognostic factor in NSCLC (hazard ratio [HR], 0.492, P = 0.001).
CONCLUSION: Our results indicate that over-expression of CHCHD2 would promote the expression of HIF-1α to adapt the hypoxia microenviroment in NSCLC and CHCHD2 could serves as a prognostic biomarker in NSCLC.

Keywords: CHCHD2; HIF-1α; Non-small cell lung cancer; Prognostic

DOI: https://doi.org/10.1186/s12890-020-1079-0

JCI Insight. 2020 Feb 13. pii: 131596. [Epub ahead of print]5(3):

GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling.

Chen WL, Jin X, Wang M, Liu D, Luo Q, Tian H, Cai L, Meng L, Bi R, Wang L, Xie X, Yu G, Li L, Dong C, Cai Q, Jia W, Wei W, Jia L.

Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.

Keywords: Lung cancer; Metabolism

DOI: https://doi.org/10.1172/jci.insight.131596

Mol Biol Rep. 2020 Feb 13.

Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation.

Spampinato M, Sferrazzo G, Pittalà V, Di Rosa M, Vanella L, Salerno L, Sorrenti V, Carota G, Parrinello N, Raffaele M, Tibullo D, Li Volti G, Barbagallo I.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.

Keywords: Glutathione; Heme oxygenase; Lung cancer; Oxidative stress

DOI: https://doi.org/10.1007/s11033-020-05292-y