Proteinase-activated Receptor 1 and 2 under Hypoxic Stress

AbstractHypoxia is a common phenomenon in solid tumors. The roles of exosomes from hypoxic breast cancer stroma are less studied. So, the study was aimed to investigate the role of exosomes from hypoxic cancer-associated fibroblasts (CAFs) cells in breast cancer. The circRNA array analysis was performed to screen differential expressed circRNAs between hypoxic and normoxic CAFs exosomes. Candidate circHIF1A (circ_0032138) was screened out and it was confirmed that circHIF1A was up-regulated in the exosomes from hypoxic CAFs and their exosomes. Through investigating cellular functions including cell proliferation and stem cell features, it was demonstrated that hypoxic CAFs exosomes transferred circHIF1A into breast cancer cells, which played an important role in cancer stem cell properties sponging miR-580-5p by regulating CD44 expression. In a summary, circHIF1A from hypoxic CAFs exosomes played an important role in stem cell properties of breast cancer. CircHIF1A may act as a target molecule of breast cancer therapy.

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Disruption of the Complex between GAPDH and Hsp70 Sensitizes C6 Glioblastoma Cells to Hypoxic Stress

International Journal of Molecular Sciences ◽

10.3390/ijms22041520 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1520

Author(s):

Marina A. Mikeladze ◽

Elizaveta A. Dutysheva ◽

Victor G. Kartsev ◽

Boris A. Margulis ◽

Irina V. Guzhova ◽

...

Keyword(s):

Cell Death ◽

Hypoxic Stress ◽

C6 Cells ◽

Tumor Resistance ◽

Glioblastoma Cells ◽

Enzyme Expression ◽

Hsp70 Chaperone ◽

Therapeutic Tools ◽

Enzyme Molecules

Hypoxia, which commonly accompanies tumor growth, depending on its strength may cause the enhancement of tumorigenicity of cancer cells or their death. One of the proteins targeted by hypoxia is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and we demonstrated here that hypoxia mimicked by treating C6 rat glioblastoma cells with cobalt chloride caused an up-regulation of the enzyme expression, while further elevation of hypoxic stress caused the enzyme aggregation concomitantly with cell death. Reduction or elevation of GAPDH performed with the aid of specific shRNAs resulted in the augmentation of the tumorigenicity of C6 cells or their sensitization to hypoxic stress. Another hypoxia-regulated protein, Hsp70 chaperone, was shown to prevent the aggregation of oxidized GAPDH and to reduce hypoxia-mediated cell death. In order to release the enzyme molecules from the chaperone, we employed its inhibitor, derivative of colchicine. The compound was found to substantially increase aggregation of GAPDH and to sensitize C6 cells to hypoxia both in vitro and in animals bearing tumors with distinct levels of the enzyme expression. In conclusion, blocking the chaperonic activity of Hsp70 and its interaction with GAPDH may become a promising strategy to overcome tumor resistance to multiple environmental stresses and enhance existing therapeutic tools.

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High Plasma Cystine Levels Are Associated with Blood Pressure and Reversed by CPAP in Patients with Obstructive Sleep Apnea

Journal of Clinical Medicine ◽

10.3390/jcm10071387 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1387

Author(s):

Raphael Boneberg ◽

Anita Pardun ◽

Lena Hannemann ◽

Olaf Hildebrandt ◽

Ulrich Koehler ◽

...

Keyword(s):

Blood Pressure ◽

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Mononuclear Cells ◽

Vascular Risk Factor ◽

High Plasma ◽

Apnea Hypopnea Index ◽

Hypoxic Stress ◽

Peripheral Blood Mononuclear ◽

Obstructive Sleep

Obstructive sleep apnea (OSA) independent of obesity (OBS) imposes severe cardiovascular risk. To what extent plasma cystine concentration (CySS), a novel pro-oxidative vascular risk factor, is increased in OSA with or without OBS is presently unknown. We therefore studied CySS together with the redox state and precursor amino acids of glutathione (GSH) in peripheral blood mononuclear cells (PBMC) in untreated male patients with OSA (apnea-hypopnea-index (AHI) > 15 h−1, n = 28) compared to healthy male controls (n = 25) stratifying for BMI ≥ or < 30 kg m−2. Fifteen OSA patients were reassessed after 3–5-months CPAP. CySS correlated with cumulative time at an O2-saturation <90% (Tu90%) (r = 0.34, p < 0.05) beside BMI (r = 0.58, p < 0.001) and was higher in subjects with “hypoxic stress” (59.4 ± 2.0 vs. 50.1 ± 2.7 µM, p < 0.01) defined as Tu90% ≥ 15.2 min (corresponding to AHI ≥ 15 h−1). Moreover, CySS significantly correlated with systolic (r = 0.32, p < 0.05) and diastolic (r = 0.31, p < 0.05) blood pressure. CPAP significantly lowered CySS along with blood pressure at unchanged BMI. Unexpectedly, GSH antioxidant capacity in PBMC was increased with OSA and reversed with CPAP. Plasma CySS levels are increased with OSA-related hypoxic stress and associated with higher blood pressure. CPAP decreases both CySS and blood pressure. The role of CySS in OSA-related vascular endpoints and their prevention by CPAP warrants further studies.

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Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Cells ◽

10.3390/cells10010097 ◽

2021 ◽

Vol 10 (1) ◽

pp. 97

Author(s):

Odeya Marciano ◽

Linoy Mehazri ◽

Sally Shpungin ◽

Alexander Varvak ◽

Eldad Zacksenhaus ◽

...

Keyword(s):

Cancer Cells ◽

Aerobic Glycolysis ◽

Metastatic Cancer ◽

Carcinoma Cells ◽

Metabolic Adaptation ◽

Hypoxic Stress ◽

Lung Carcinoma Cells ◽

Metabolic Role ◽

Highly Sensitive ◽

Anticancer Treatment

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.

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The effect of dexamethasone and hypoxic stress on MC3T3-E1 cells

Frontiers in Bioscience ◽

10.2741/3883 ◽

2011 ◽

Vol 16 (1) ◽

pp. 2747 ◽

Cited By ~ 4

Author(s):

Zhen-Hong Zhu

Keyword(s):

Hypoxic Stress

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Hypoxic stress visualized in the cervical spinal cord of ALS patients

Neurological Research ◽

10.1080/01616412.2020.1866383 ◽

2020 ◽

pp. 1-5

Author(s):

Toru Yamashita ◽

Tetsuhiro Hatakeyama ◽

Kota Sato ◽

Yusuke Fukui ◽

Nozomi Hishikawa ◽

...

Keyword(s):

Spinal Cord ◽

Cervical Spinal Cord ◽

Hypoxic Stress ◽

Als Patients

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Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

Pharmacology ◽

10.1159/000480405 ◽

2017 ◽

Vol 101 (1-2) ◽

pp. 64-71 ◽

Cited By ~ 3

Author(s):

Tetsuhiro Horie ◽

Kazuya Fukasawa ◽

Takashi Iezaki ◽

Gyujin Park ◽

Yuki Onishi ◽

...

Keyword(s):

Amino Acid ◽

Hypoxia Inducible Factor ◽

Amino Acid Transporters ◽

Hypoxic Stress ◽

Gene Encoding ◽

Brown Adipocytes ◽

Hypoxia Inducible Factor 1Α ◽

Brown Adipose

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

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