bims-almceb 2021-01-31 papers

Redox Biol. 2021 Jan 21. pii: S2213-2317(21)00018-5. [Epub ahead of print] 101870

Mitochondrial metabolism-mediated redox regulation in cancer progression.

Cancer cells display abnormal metabolic activity as a result of activated oncogenes and loss of tumor suppressor genes. The Warburg Effect is a common metabolic feature of cancer that involves a preference for aerobic glycolysis over oxidative phosphorylation to generate ATP and building blocks for biosynthesis. However, emerging evidence indicates that mitochondrial metabolic pathways are also reprogrammed in cancer and play vital roles in bioenergetics, biosynthesis, and managing redox homeostasis. The mitochondria act a central hub for metabolic pathways that generate ATP and building blocks for lipid, nucleic acid and protein biosynthesis. However, mitochondrial respiration is also a leading source of reactive oxygen species that can damage cellular organelles and trigger cell death if levels become too high. In general, cancer cells are reported to have higher levels of reactive oxygen species than their non-cancerous cells of origin, and therefore must employ diverse metabolic strategies to prevent oxidative stress. However, mounting evidence indicates that the metabolic profiles between proliferative and disseminated cancer cells are not the same. In this review, we will examine mitochondrial metabolic pathways, such as glutaminolysis, that proliferative and disseminated cancer cells utilize to control their redox status.

Keywords: Cancer progression; Glutaminolysis; Mitochondria metabolism; Redox homeostasis

DOI: https://doi.org/10.1016/j.redox.2021.101870

Trends Cancer. 2021 Jan 25. pii: S2405-8033(20)30341-1. [Epub ahead of print]

The Role of the Microenvironment and Immune System in Regulating Stem Cell Fate in Cancer.

L Paige Ferguson, Emily Diaz, Tannishtha Reya.

Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further discuss the role of cancer stem cells in immune evasion through the course of metastasis, dormancy, and relapse. Understanding the niche in which cancer stem cells live and the signals that sustain them may lead to new strategies that target them by disrupting microenvironmental support.

Keywords: Cancer; Metastasis; Stem cell; Therapy resistance; Tumor microenvironment

DOI: https://doi.org/10.1016/j.trecan.2020.12.014

J Hepatol. 2021 Jan 20. pii: S0168-8278(21)00024-6. [Epub ahead of print]

Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma.

BACKGROUND AND AIMS: Little is known about the metabolic regulation of cancer stem cells (CSC) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stem state in CCA.
METHODS: The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 and CCLP1) and compared to cells cultured in monolayer. Extracellular flux analysis was examined by Seahorse technology and high-resolution respirometry. In patients with CCA, expression of factors related to mitochondrial metabolism was analyzed for possible correlation with clinical parameters.
RESULTS: Metabolic analyses revealed a more efficient respiratory phenotype in CCA-SPH than in monolayers, due to mitochondrial oxidative phosphorylation. CCA-SPH showed high mitochondrial membrane potential and elevated mitochondrial mass, and over-expressed peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, a master regulator of mitochondrial biogenesis. Targeting mitochondrial complex I in CCA-SPH by metformin, or PGC-1α silencing or pharmacologic inhibition (SR-18292) impaired spherogenicity and expression of markers related to the CSC phenotype, pluripotency, and epithelial-mesenchymal transition. In mice with tumor xenografts generated by injection of CCA-SPH, administration of metformin or SR-18292 significantly reduced tumor growth and determined a phenotype more similar to tumors originated from cells grown in monolayer. In CCA patients, expression of PGC-1α was correlated to expression of mitochondrial complex II and of stem-like genes. Patients with higher PGC-1α expression by immunostaining had lower overall survival (OS) and progression-free survival, higher angioinvasion and faster recurrence. In GSEA analysis, CCA patients with high levels of mitochondrial Complex II had shorter OS and time to recurrence.
CONCLUSIONS: The CCA stem-subset has a more efficient respiratory phenotype and depends on mitochondrial oxidative metabolism and PGC-1α to maintain CSC features.
LAY SUMMARY: The growth of many cancers is sustained by a specific type of cells with more embryonic characteristics, termed as 'cancer stem cells'. These cells have been described in cholangiocarcinoma, a type of liver cancer with poor prognosis and limited therapeutic approaches. We demonstrate that cancer stem cells in cholangiocarcinoma have different metabolic features, and use mitochondria, an organelle located within the cells, as the major source of energy. We also identify PGC-1α, a molecule which regulates the biology of mitochondria, as a possible new target to be explored for developing new treatments for cholangiocarcinoma.

Keywords: CCLP1; HUCCT1; OXPHOS; PGC-1α; SR-18292

DOI: https://doi.org/10.1016/j.jhep.2020.12.031

Acta Pharmacol Sin. 2021 Jan 28.

Structure, regulation, and biological functions of TIGAR and its role in diseases.

Jie Tang, Lei Chen, Zheng-Hong Qin, Rui Sheng.

TIGAR (TP53-induced glycolysis and apoptosis regulator) is the downstream target gene of p53, contains a functional sequence similar to 6-phosphofructose kinase/fructose-2, 6-bisphosphatase (PFKFB) bisphosphatase domain. TIGAR is mainly located in the cytoplasm; in response to stress, TIGAR is translocated to nucleus and organelles, including mitochondria and endoplasmic reticulum to regulate cell function. P53 family members (p53, p63, and p73), some transcription factors (SP1 and CREB), and noncoding miRNAs (miR-144, miR-885-5p, and miR-101) regulate the transcription of TIGAR. TIGAR mainly functions as fructose-2,6-bisphosphatase to hydrolyze fructose-1,6-diphosphate and fructose-2,6-diphosphate to inhibit glycolysis. TIGAR in turn facilitates pentose phosphate pathway flux to produce nicotinamide adenine dinucleotide phosphate (NADPH) and ribose, thereby promoting DNA repair, and reducing intracellular reactive oxygen species. TIGAR thus maintains energy metabolism balance, regulates autophagy and stem cell differentiation, and promotes cell survival. Meanwhile, TIGAR also has a nonenzymatic function and can interact with retinoblastoma protein, protein kinase B, nuclear factor-kappa B, hexokinase 2, and ATP5A1 to mediate cell cycle arrest, inflammatory response, and mitochondrial protection. TIGAR might be a potential target for the prevention and treatment of cardiovascular and neurological diseases, as well as cancers.

Keywords: NADPH; TIGAR; cancer; cerebral ischemia–reperfusion; myocardial infarction; neurological disorders; pentose phosphate pathway

DOI: https://doi.org/10.1038/s41401-020-00588-y

Front Cell Dev Biol. 2020 ;8 625943

Niche Modulation of IGF-1R Signaling: Its Role in Stem Cell Pluripotency, Cancer Reprogramming, and Therapeutic Applications.

Pei-Chin Chen, Yung-Che Kuo, Cheng-Ming Chuong, Yen-Hua Huang.

Stem cells work with their niches harmoniously during development. This concept has been extended to cancer pathology for cancer stem cells (CSCs) or cancer reprogramming. IGF-1R, a classical survival signaling, has been shown to regulate stem cell pluripotency, CSCs, or cancer reprogramming. The mechanism underlying such cell fate determination is unclear. We propose the determination is due to different niches in embryo development and tumor malignancy which modulate the consequences of IGF-1R signaling. Here we highlight the modulations of these niche parameters (hypoxia, inflammation, extracellular matrix), and the targeted stem cells (embryonic stem cells, germline stem cells, and mesenchymal stem cells) and CSCs, with relevance to cancer reprogramming. We organize known interaction between IGF-1R signaling and distinct niches in the double-sided cell fate with emerging trends highlighted. Based on these new insights, we propose that, through targeting IGF-1R signaling modulation, stem cell therapy and cancer stemness treatment can be further explored.

Keywords: IGF-1R; cancer stemness; extracellular matrix; hypoxia; inflammation; niche; stem cells

DOI: https://doi.org/10.3389/fcell.2020.625943

Acta Oncol. 2021 Jan 25. 1-3

Identification of a novel resistance mechanism in venetoclax treatment and its prediction in chronic lymphocytic leukemia.

Ferenc Takács, Gábor Mikala, Noémi Nagy, Andrea Reszegi, Ágnes Czeti, Gábor Szalóki, Gábor Barna.

BACKGROUND: The Bcl-2 inhibitor venetoclax has been recently introduced into the treatment of chronic lymphocytic leukemia. Venetoclax is a highly effective drug, however acquired resistance may make long-term treatment challenging. In our study, we present potential novel resistance mechanisms and prognostic markers that are potentially able to predict the early appearance of the resistance.
MATERIAL AND METHODS: Repeated complete blood counts, flow cytometric measurements, and physical examinations were performed during the patient follow-up. Clinical and laboratory parameters showed that the patient developed clinical resistance to venetoclax on day 450 of therapy. Resistance mutation analysis (D103Y) and apoptosis arrays from samples at the time of resistance were done.
RESULTS: We were able to identify the resistance mutations just a very low variant allele frequency level from the resistant samples. Furthermore we detected increased Bcl-2 expression in peripheral blood (PB), and XIAP overexpression in bone marrow (BM) that could lead to venetoclax resistance. We examined the immunophenotype of CLL cells and recognized that while the expression of CD86 did not change until day 270 of the treatment, since then its expression steadily increased. Moreover, we compared the expression of CD86 in the resistant PB and BM samples and did not find a notable difference between the compartments.
CONCLUSION: Our results imply that CLL cells may try to avoid the apoptotic effect of venetoclax through increased CD86 expression by activating antiapoptotic mechanisms. Confirmatory experiments are still required to unequivocally prove that CD86 is a prognostic marker, however, its predictive property during the venetoclax treatment is promising.

Keywords: Chronic lymphocytic leukemia; drug resistance; flow cytometry; targeted therapy

DOI: https://doi.org/10.1080/0284186X.2021.1878388

Biology (Basel). 2021 Jan 23. pii: 85. [Epub ahead of print]10(2):

Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism.

Ibrahim H Polat, Míriam Tarrado-Castellarnau, Rohit Bharat, Jordi Perarnau, Adrian Benito, Roldán Cortés, Philippe Sabatier, Marta Cascante.

The pentose phosphate pathway (PPP) plays an essential role in the metabolism of breast cancer cells for the management of oxidative stress and the synthesis of nucleotides. 6-phosphogluconate dehydrogenase (6PGD) is one of the key enzymes of the oxidative branch of PPP and is involved in nucleotide biosynthesis and redox maintenance status. Here, we aimed to analyze the functional importance of 6PGD in a breast cancer cell model. Inhibition of 6PGD in MCF7 reduced cell proliferation and showed a significant decrease in glucose consumption and an increase in glutamine consumption, resulting in an important alteration in the metabolism of these cells. No difference in reactive oxygen species (ROS) production levels was observed after 6PGD inhibition, indicating that 6PGD, in contrast to glucose 6-phosphate dehydrogenase, is not involved in redox balance. We found that 6PGD inhibition also altered the stem cell characteristics and mammosphere formation capabilities of MCF7 cells, opening new avenues to prevent cancer recurrance after surgery or chemotherapy. Moreover, inhibition of 6PGD via chemical inhibitor S3 resulted in an induction of senescence, which, together with the cell cycle arrest and apoptosis induction, might be orchestrated by p53 activation. Therefore, we postulate 6PGD as a novel therapeutic target to treat breast cancer.

Keywords: 6PGD; breast cancer; cancer metabolism; pentose phosphate pathway

DOI: https://doi.org/10.3390/biology10020085

Cancers (Basel). 2021 Jan 22. pii: 401. [Epub ahead of print]13(3):

TGF-β in Cancer: Metabolic Driver of the Tolerogenic Crosstalk in the Tumor Microenvironment.

Roberta Angioni, Ricardo Sánchez-Rodríguez, Antonella Viola, Barbara Molon.

Overcoming tumor immunosuppression still represents one ambitious achievement for cancer immunotherapy. Of note, the cytokine TGF-β contributes to immune evasion in multiple cancer types, by feeding the establishment of a tolerogenic environment in the host. Indeed, it fosters the expansion and accumulation of immunosuppressive regulatory cell populations within the tumor microenvironment (TME), where it also activates resident stromal cells and enhances angiogenesis programs. More recently, TGF-β has also turned out as a key metabolic adjuster in tumors orchestrating metabolic pathways in the TME. In this review, we will scrutinize TGF-β-mediated immune and stromal cell crosstalk within the TME, with a primary focus on metabolic programs.

Keywords: TGF-β; immune-metabolism; tumor microenvironment

DOI: https://doi.org/10.3390/cancers13030401