scholarly journals Untargeted Metabolomics Identifies Key Metabolic Pathways Altered by Thymoquinone in Leukemic Cancer Cells

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1792 ◽  
Author(s):  
Asma Ahmed AlGhamdi ◽  
Mohammed Razeeth Shait Mohammed ◽  
Mazin A. Zamzami ◽  
Abdulrahman L. Al-Malki ◽  
Mohamad Hasan Qari ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metabolic Pathways ◽  
Nigella Sativa ◽  
Experimental Studies ◽  
Nucleotide Metabolism ◽  
Untargeted Metabolomics ◽  
Sphingolipid Metabolism ◽  
Cancer Cell Survival

Thymoquinone (TQ), a naturally occurring anticancer compound extracted from Nigella sativa oil, has been extensively reported to possess potent anti-cancer properties. Experimental studies showed the anti-proliferative, pro-apoptotic, and anti-metastatic effects of TQ on different cancer cells. One of the possible mechanisms underlying these effects includes alteration in key metabolic pathways that are critical for cancer cell survival. However, an extensive landscape of the metabolites altered by TQ in cancer cells remains elusive. Here, we performed an untargeted metabolomics study using leukemic cancer cell lines during treatment with TQ and found alteration in approximately 335 metabolites. Pathway analysis showed alteration in key metabolic pathways like TCA cycle, amino acid metabolism, sphingolipid metabolism and nucleotide metabolism, which are critical for leukemic cell survival and death. We found a dramatic increase in metabolites like thymine glycol in TQ-treated cancer cells, a metabolite known to induce DNA damage and apoptosis. Similarly, we observed a sharp decline in cellular guanine levels, important for leukemic cancer cell survival. Overall, we provided an extensive metabolic landscape of leukemic cancer cells and identified the key metabolites and pathways altered, which could be critical and responsible for the anti-proliferative function of TQ.

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

scholarly journals Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1366
Author(s):  
Russell Hughes ◽  
Xinyue Chen ◽  
Natasha Cowley ◽  
Penelope D. Ottewell ◽  
Rhoda J. Hawkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Accessory Cell ◽  
Cancer Cell Survival

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

scholarly journals Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

2016 ◽  
Vol 113 (35) ◽  
pp. 9810-9815 ◽  
Author(s):  
Yubao Wang ◽  
Michael Begley ◽  
Qing Li ◽  
Hai-Tsang Huang ◽  
Ana Lako ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Leucine Zipper ◽  
Apoptotic Cell ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Signaling Axis ◽  
Cancer Cell Survival

The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELK–eIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK–eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival.

scholarly journals Src Regulates Tyr20 Phosphorylation of Transferrin Receptor-1 and Potentiates Breast Cancer Cell Survival

2011 ◽  
Vol 286 (41) ◽  
pp. 35708-35715 ◽  
Author(s):  
Jinlong Jian ◽  
Qing Yang ◽  
Xi Huang
Keyword(s):  
Breast Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Transferrin Receptor ◽  
Iron Uptake ◽  
Caspase 3 ◽  
Transferrin Receptor 1 ◽  
Cancer Cell Survival

Transferrin receptor 1 (TfR1) is a ubiquitous type II membrane receptor with 61 amino acids in the N-terminal cytoplasmic region. TfR1 is highly expressed in cancer cells, particularly under iron deficient conditions. Overexpression of TfR1 is thought to meet the increased requirement of iron uptake necessary for cell growth. In the present study, we used transferrin (Tf), a known ligand of TfR1, and gambogic acid (GA), an apoptosis-inducing agent and newly identified TfR1 ligand to investigate the signaling role of TfR1 in breast cancer cells. We found that GA but not Tf induced apoptosis in a TfR1-dependent manner in breast cancer MDA-MB-231 cells. Estrogen receptor-positive MCF-7 cells lack caspase-3 and were not responsive to GA treatment. GA activated the three major signaling pathways of the MAPK family, as well as caspase-3, -8, and Poly(ADP-ribose)polymerase apoptotic pathway. Interestingly, only Src inhibitor PP2 greatly sensitized the cells to GA-mediated apoptosis. Further investigations by confocal fluorescence microscopy and immunoprecipitation revealed that Src and TfR1 are constitutively bound. Using TfR1-deficient CHO TRVB cells, point mutation studies showed that Tyr20 within the 20YTRF23 motif of the cytoplasmic region of TfR1 is the phosphorylation site by Src. TfR1 Tyr20 phosphomutants were more sensitive to GA-mediated apoptosis. Our results indicate that, albeit its iron uptake function, TfR1 is a signaling molecule and tyrosine phosphorylation at position 20 by Src enhances anti-apoptosis and potentiates breast cancer cell survival.

scholarly journals Adipocytes Promote Breast Cancer Cell Survival and Migration through Autophagy Activation

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3917
Author(s):  
Dorine Bellanger ◽  
Cléa Dziagwa ◽  
Cyrille Guimaraes ◽  
Michelle Pinault ◽  
Jean-François Dumas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
White Adipose Tissue ◽  
Breast Cancer Cells ◽  
Cancer Cell Survival

White adipose tissue interacts closely with breast cancers through the secretion of soluble factors such as cytokines, growth factors or fatty acids. However, the molecular mechanisms of these interactions and their roles in cancer progression remain poorly understood. In this study, we investigated the role of fatty acids in the cooperation between adipocytes and breast cancer cells using a co-culture model. We report that adipocytes increase autophagy in breast cancer cells through the acidification of lysosomes, leading to cancer cell survival in nutrient-deprived conditions and to cancer cell migration. Mechanistically, the disturbance of membrane phospholipid composition with a decrease in arachidonic acid content is responsible for autophagy activation in breast cancer cells induced by adipocytes. Therefore, autophagy might be a central cellular mechanism of white adipose tissue interactions with cancer cells and thus participate in cancer progression.

scholarly journals Exploring cysteine regulation in cancer cell survival with a highly specific “Lock and Key” fluorescent probe for cysteine

2019 ◽  
Vol 10 (43) ◽  
pp. 10065-10071 ◽  
Author(s):  
Jing Liu ◽  
Mengxing Liu ◽  
Hongxing Zhang ◽  
Xuehong Wei ◽  
Juanjuan Wang ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cells ◽  
Fluorescent Probe ◽  
Cancer Cell ◽  
Cancer Cell Survival

Using a highly specific “lock and key” fluorescent Cys probe, we confirmed that targeting Cys metabolism to deplete intracellular Cys is a more potent strategy to sensitize cancer cells to chemotherapies.

scholarly journals mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

2018 ◽  
Vol 19 (10) ◽  
pp. 3267 ◽  
Author(s):  
Mio Harachi ◽  
Kenta Masui ◽  
Yukinori Okamura ◽  
Ryota Tsukui ◽  
Paul Mischel ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Cancer Cell Survival

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.

scholarly journals Nuclear lamin A/C promotes cancer cell survival and lung metastasis without restricting transendothelial migration

2020 ◽  
Author(s):  
Francesco Roncato ◽  
Ofer Regev ◽  
Sara W. Feigelson ◽  
Sandeep Kumar Yadav ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Nuclear Lamina ◽  
Transendothelial Migration ◽  
Lamin A ◽  
Primary Tumors ◽  
Cancer Cell Survival

AbstractThe mechanisms by which the nuclear lamina of tumor cells controls their migration and survival are poorly understood. Lamin A and its variant lamin C are key nuclear lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C levels in two metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, elevated nuclear deformability and reduced heterochromatin. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown. Both cancer cells with lamin A/C knockdown grew normally in primary tumors and in vitro on rigid surfaces. Strikingly, however, both lamin A/C deficient melanoma and breast cancer cells grew poorly in 3D spheroids expanded in soft agar cultures. Experimental lung metastasis of both lamin A/C knockdown cells was also markedly reduced. Taken together, our results suggest that high content of lamin A/C in multiple cancer cells promotes cancer cell survival and ability to generate lung metastasis without compromising cancer cell emigration from lung vessels.

scholarly journals Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids

2021 ◽  
Vol 22 (5) ◽  
pp. 2466
Author(s):  
Kenza Mamouni ◽  
Georgios Kallifatidis ◽  
Bal L. Lokeshwar
Keyword(s):  
Prostate Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Mitochondrial Metabolism ◽  
Metabolic Reprogramming ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Cancer Cell Survival ◽  
The Impact

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.

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