bims-meluca 2020-01-19 papers

Cells. 2020 Jan 14. pii: E205. [Epub ahead of print]9(1):

The Reverse Warburg Effect is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts.

Duda P, Janczara J, McCubrey JA, Gizak A, Rakus D.

Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts' ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactate and pyruvate-a process known as the reverse Warburg effect. We demonstrate that these changes result from a fibroblasts-stimulated increase in the expression of fructose bisphosphatase (Fbp) in cancer cells and the consequent modulation of Hif1α function. We show that, in contrast to current beliefs, in lung cancer cells, the predominant and strong interaction with the Hif1α form of Fbp is not the liver (Fbp1) but in the muscle (Fbp2) isoform. Since Fbp2 oligomerization state and thus, its role is regulated by AMP and NAD+-crucial indicators of cellular metabolic conditions-we hypothesize that the Hif1α-dependent regulation of the metabolism in cancer is modulated through Fbp2, a sensor of the energy and redox state of a cell.

Keywords: fructose 1,6-bisphosphatase 2; glycolysis; hypoxia-inducible factor-1α; lung cancer

DOI: https://doi.org/10.3390/cells9010205

Int J Clin Exp Pathol. 2018 ;11(3): 1575-1580

Influence of SIRT6 regulation of cellular glycometabolism on radiosensitivity of non-small-cell lung cancer A549 cells.

Cai Y, Sheng Z, Chen Y, Wang J.

OBJECTIVE: To investigate the influence of SIRT6 mediated regulation of cellular glycometabolism on radiosensitivity of A549 non-small-cell lung cancer (NSCLC) cells.METHODS: Ad-SIRT6 adenovirus vector overexpressed SIRT6 and was established and divided into a control group, a zero-load group (Ad-null), and an overexpression group (Ad-SIRT6). The virus concentration of the Ad-null group and the Ad-SIRT6 group was 200 pfu/cell. The survival factor (SF) after X-ray irradiation of 0, 2, 4, 6, 8, and 10 Gy in three groups was detected by clone formation and cell cycle and apoptosis after 4 Gy X-ray irradiation for 48 hours in the three groups was detected by flow cytometry. Expression levels of pyruvate kinase (PKM), lactate dehydrogenase (LDHA), and hexokinase (HK) after 4 Gy X-ray irradiation of 48 h were detected by qPCR. The glucose level after consumption of (1×106) cells in the medium was detected by a glucose kit.
RESULTS: Compared with the control group and the Ad-null group, SFs after X-ray irradiation of 4-10 Gy in the Ad-SIRT6 group were decreased (P<0.05). A sensitization enhancement ratio of the Ad-SIRT group/the control group was 1.451. After 4 Gy X-ray irradiation of 48 h, the cell ratio and apoptosis rate in G1 phase were increased in the Ad-SIRT6 group, with statistical significance when compared with the other two groups (P<0.05). Compared with the control group and the Ad-null group, levels of PKM, LDHA, and HK mRNA in Ad-SIRT6 group were decreased (P<0.05) and the remaining glucose in the medium was increased (P<0.05).
CONCLUSION: Overexpression of SIRT6 can inhibit key-enzyme generation in A549 cells to inhibit glycolysis, enhance the radiosensitivity, and lead to G0/G1 phase block as well as cell apoptosis.

Keywords: SIRT6; glycolysis; non-small-cell lung cancer; radiosensitivity

J Biomed Sci. 2020 Jan 13. 27(1): 5

Involvement of collagen XVII in pluripotency gene expression and metabolic reprogramming of lung cancer stem cells.

Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Li AF, Hung SC.

BACKGROUND: Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms.METHODS: The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients.
RESULTS: We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin-332 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients.
CONCULSIONS: These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment.

Keywords: Collagen XVII; Hexokinase 2; Lung cancer stem cells; Metabolic reprogramming; Oct4

DOI: https://doi.org/10.1186/s12929-019-0593-y