bims-meluca 2021-09-19 papers

Free Radic Biol Med. 2021 Sep 11. pii: S0891-5849(21)00720-6. [Epub ahead of print]

PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells.

Gabriele Bluemel, Mélanie Planque, Corina T Madreiter-Sokolowski, Theresa Haitzmann, Andelko Hrzenjak, Wolfgang F Graier, Sarah-Maria Fendt, Horst Olschewski, Katharina Leithner.

Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. Mitochondrial phosphoenolpyruvate carboxykinase, PCK2, has recently been found to mediate partial gluconeogenesis and hence anabolic metabolism in glucose starved cancer cells. Here we show that PCK2 acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived human lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, enhancing the TCA cycle by PCK2 inhibition severely reduced colony formation of lung cancer cells under starvation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool in starved cancer cells besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and shows that PCK2 confers protection against respiration-induced oxidative stress.

Keywords: Adaptation; Cancer metabolism; Gluconeogenesis; Metabolic flexibility; Mitochondria; Redox balance; Respiration

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.09.007

Aging (Albany NY). 2021 Sep 16. 13(undefined):

Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells.

Tharcisio Citrangulo Tortelli, Rodrigo Esaki Tamura, Mara de Souza Junqueira, Janio da Silva Mororó, Silvina Odete Bustos, Renato Jose Mendonça Natalino, Shonagh Russell, Laurent Désaubry, Bryan Eric Strauss, Roger Chammas.

Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.

Keywords: Jarid1b; NSCLC; cisplatin; metformin; p53

DOI: https://doi.org/10.18632/aging.203528

J Cancer Res Ther. 2021 Jul-Sep;17(4):17(4): 925-930

Prognostic impact of the 18F-fluorodeoxyglucose positron-emission tomography/computed tomography metabolic parameters and correlation with hematological inflammatory markers in lung cancer.

Sibel Goksel, Arzu Cengiz, Hakan Ozturk, Yakup Yurekli.

Introduction: Hematological inflammatory markers and metabolic parameters in positron-emission tomography/computed tomography (PET/CT) are important indicators predicting the prognosis of the disease in lung cancer as in many cancers. This study aimed to evaluate the correlation between pretreatment hematological inflammatory markers and PET/CT metabolic parameters in nonsmall cell lung cancer (NSCLC) patients and to predict the prognostic value of these parameters.Materials and Methods: A total of 132 patients with diagnosed NSCLC who underwent PET/CT at staging were retrospectively evaluated. Hematological parameters were obtained from the hemogram taken no more than 2 weeks prior to PET/CT. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) were recorded. Maximum standard uptake value, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. Clinical stage, tumor pathology, and overall survival were analyzed with these parameters.
Results: NLR and PLR were significantly positively correlated with MTV and TLG (all P < 0.001), MPV was negatively correlated with TLG (P = 0.021). While TLG, MTV, NLR, and PLR were increased in advanced stage disease, MPV was decreased. Univariate Cox-regression analysis demonstrated that greater age (P = 0.015), advanced stage (P < 0.001), low MPV (P = 0.017), high NLR (P < 0.001), PLR (P < 0.001), MTV (P = 0.004), TLG (P = 0.001) values, multivariate Cox-regression analysis revealed that NLR (P < 0.001) and advanced stage (P < 0.001) were significant predictors of poor prognosis in patients with NSCLC.
Conclusions: There were significant associations between hematological inflammatory markers and PET/CT metabolic parameters in the patients with NSCLC at the time of diagnosis. These indicators can contribute to predicting prognosis in patients with NSCLC.

Keywords: Hematological parameter; metabolic tumor volume; nonsmall cell lung cancer; prognosis; total lesion glycolysis

DOI: https://doi.org/10.4103/jcrt.JCRT_1046_20

Genes Dis. 2021 Nov;8(6): 731-745

NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation.

Xiaoguang Liu, Yilei Zhang, Li Zhuang, Kellen Olszewski, Boyi Gan.

Cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT) plays a key role in antioxidant defense by mediating cystine uptake, promoting glutathione synthesis, and maintaining cell survival under oxidative stress conditions. Recent studies showed that, to prevent toxic buildup of highly insoluble cystine inside cells, cancer cells with high expression of SLC7A11 (SLC7A11high) are forced to quickly reduce cystine to more soluble cysteine, which requires substantial NADPH supply from the glucose-pentose phosphate pathway (PPP) route, thereby inducing glucose- and PPP-dependency in SLC7A11high cancer cells. Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH "debt", redox "bankruptcy", and subsequent cell death. This review summarizes our current understanding of NADPH-generating and -consuming pathways, discusses the opposing role of SLC7A11 in protecting cells from oxidative stress-induced cell death such as ferroptosis but promoting glucose starvation-induced cell death, and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation. A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.

Keywords: Cysteine; Cystine; NADPH; Pentose phosphate pathway; SLC7A11; xCT

DOI: https://doi.org/10.1016/j.gendis.2020.11.010