Protein kinase D1 regulates hypoxic metabolism through HIF-1α and glycolytic enzymes incancer cells

Chen, Jiao; Cui, Bomiao; Fan, Yujiang; Li, Xiaoying; Li, Qian; Du, Ye; Feng, Yun; Zhang, Ping

doi:10.3892/or.2018.6479

Cited by 11 publications

(20 citation statements)

References 43 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, these results corroborated with recently published studies suggesting that protein kinase D1 regulates HIF-1α in the human tongue squamous cell carcinoma cells. 34 mTOR is the conserved serine/threonine kinase that regulates the proliferation and metabolism in cells. mTOR exists in two distinct complexes with different protein components and downstream substrates: mTOR complex C1 and C2.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1

et al. 2019

View full text Add to dashboard Cite

BACKGROUND: Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance. METHODS: PKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes. RESULTS: PKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations. CONCLUSION: This study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Normal cells or Glut-1 and/or HIF-1α knockout cells were incubated under hypoxic or normoxic conditions. After treatment with or without 12 Gy X-ray irradiation, cells were incubated with medium containing 18 F-fluorodeoxyglucose (FDG) for an additional 3 h. They were then digested and collected. The intracellular (C in ) and extracellular (C out ) radioactivity levels were determined using a gamma radioimmunoassay counter (WIZARD2, PerkinElmer).…”

Section: Glucose Uptake In Vitromentioning

confidence: 99%

Effect of Glut‐1 and HIF‐1α double knockout by CRISPR/CAS9 on radiosensitivity in laryngeal carcinoma via the PI3K/Akt/mTOR pathway

Bao

Zhong

Shen

et al. 2022

J Cellular Molecular Medi

View full text Add to dashboard Cite

Hypoxic resistance is the main obstacle to radiotherapy for laryngeal carcinoma. Our previous study indicated that hypoxia‐inducible factor 1α (HIF‐1α) and glucose transporter 1 (Glut‐1) double knockout reduced tumour biological behaviour in laryngeal carcinoma cells. However, their radioresistance mechanism remains unclear. In this study, cell viability was determined by CCK8 assay. Glucose uptake capability was evaluated by measurement of 18F‐fluorodeoxyglucose radioactivity. A tumour xenograft model was established by subcutaneous injection of Tu212 cells. Tumour histopathology was determined by haematoxylin and eosin staining, immunohistochemical staining, and TUNEL assays. Signalling transduction was evaluated by Western blotting. We found that hypoxia induced radioresistance in Tu212 cells accompanied by increased glucose uptake capability and activation of the PI3K/Akt/mTOR pathway. Inhibition of PI3K/Akt/mTOR activity abolished hypoxia‐induced radioresistance and glucose absorption. Mechanistic analysis revealed that hypoxia promoted higher expressions of HIF‐1α and Glut‐1. Moreover, the PI3K/Akt/mTOR pathway was a positive mediator of HIF‐1α and/or Glut‐1 in the presence of irradiation. HIF‐1α and/or Glut‐1 knockout significantly reduced cell viability, glucose uptake and PI3K/Akt/mTOR activity, all of which were induced by hypoxia in the presence of irradiation. In vivo analysis showed that knockout of HIF‐1α and/or Glut‐1 also inhibited tumour growth by promoting cell apoptosis, more robustly compared with the PI3K inhibitor wortmannin, particularly in tumours with knockout of both HIF‐1α and Glut‐1. HIF‐1α and/or Glut‐1 knockout also abrogated PI3K/Akt/mTOR signalling transduction in tumour tissues, in a manner similar to wortmannin. HIF‐1α and/or Glut‐1 knockout facilitated radiosensitivity in laryngeal carcinoma Tu212 cells by regulation of the PI3K/Akt/mTOR pathway.

show abstract

“…Hypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically to a decrease in oxygen, or hypoxia (15). HIF-1α regulates the transcription of >40 genes, including erythropoietin (16), glucose transporters (17), glycolytic enzymes (18), vascular endothelial growth factor (VEGF) (19) and other genes whose protein products increase oxygen delivery (20) or facilitate metabolic adaptation to hypoxia (21). In these complex pathophysiological mechanisms, the stable presence of HIF-1α in the nucleus and the continued activation of the HIF-1α/VEGF signaling pathway depend on the balance of ubiquitination and small ubiquitin-related modifier (SUMO) modification of HIF-1α (22,23).…”

Section: Astragaloside IV Improves Angiogenesis Under Hypoxic Conditions By Enhancing Hypoxia-inducible Factor-1α Sumoylationmentioning

confidence: 99%

Astragaloside IV improves angiogenesis under hypoxic conditions by enhancing hypoxia‑inducible factor‑1α SUMOylation

Wang

Chu

et al. 2021

Mol Med Rep

View full text Add to dashboard Cite

Improving angiogenic capacity under hypoxic conditions is essential for improving the survival of skin grafts, as they often lack the necessary blood supply. The stable expression levels of hypoxia-inducible factor-1α (HIF-1α) in the nucleus directly affect the downstream vascular endothelial growth factor (VEGF) signaling pathway and regulate angiogenesis in a hypoxic environment. Astragaloside IV (AS-IV), an active component isolated from Astragalus membranaceus , has multiple biological effects including antioxidant and anti-diabetic effects, and the ability to provide protection from cardiovascular damage. However, the mechanisms underlying these effects have not previously been elucidated. The present study investigated whether AS-IV promotes angiogenesis via affecting the balance between ubiquitination and small ubiquitin-related modifier (SUMO) modification of HIF-1α. The results demonstrated that persistent hypoxia induces changes in expression levels of HIF-1α protein and significantly increases the proportion of dysplastic blood vessels. Further western blotting experiments showed that rapid attenuation and delayed compensation of SUMO1 activity is one of the reasons for the initial increase then decrease in HIF-1α levels. SUMO1 overexpression stabilized the presence of HIF-1α in the nucleus and decreased the extent of abnormal blood vessel morphology observed following hypoxia. AS-IV induces vascular endothelial cells to continuously produce SUMO1, stabilizes the HIF-1α/VEGF pathway and improves angiogenesis in hypoxic conditions. In summary, the present study confirmed that AS-IV stimulates vascular endothelial cells to continuously resupply SUMO1, stabilizes the presence of HIF-1α protein and improves angiogenesis in adverse hypoxic conditions, which may improve the success rate of flap graft surgery following trauma or burn.

show abstract

Protein kinase D1 regulates hypoxic metabolism through HIF-1α and glycolytic enzymes incancer cells

Cited by 11 publications

References 43 publications

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1

Protein kinase D1 regulates metabolic switch in pancreatic cancer via modulation of mTORC1

Effect of Glut‐1 and HIF‐1α double knockout by CRISPR/CAS9 on radiosensitivity in laryngeal carcinoma via the PI3K/Akt/mTOR pathway

Astragaloside IV improves angiogenesis under hypoxic conditions by enhancing hypoxia‑inducible factor‑1α SUMOylation

Contact Info

Product

Resources

About