scholarly journals Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex

2021 ◽  
Author(s):  
Tian Xia ◽  
Di Chen ◽  
Xiaolong Liu ◽  
Huan Qi ◽  
Wen Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
Growth Factors ◽  
Growth Factor ◽  
Cancer Progression ◽  
Cancer Cell Proliferation ◽  
Breast Cancers ◽  
Ampk Activation ◽  
Glucose Starvation ◽  
Inhibitory Mechanism

Midkine (MDK), an extracellular growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with PRKAA1 (encoding AMPKα1) expression and phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

scholarly journals RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 860
Author(s):  
Chia-Herng Yue ◽  
Muhammet Oner ◽  
Chih-Yuan Chiu ◽  
Mei-Chih Chen ◽  
Chieh-Lin Teng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Medullary Thyroid Cancer ◽  
Receptor Protein ◽  
Cancer Cell Proliferation ◽  
Thyroid Cancer Cell ◽  
Cancer Proliferation ◽  
Medullary Thyroid

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.

scholarly journals Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.

1996 ◽  
Vol 135 (6) ◽  
pp. 1633-1642 ◽  
Author(s):  
S Miyamoto ◽  
H Teramoto ◽  
J S Gutkind ◽  
K M Yamada
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Transient Activation

Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.

scholarly journals How can food extracts consumed in the Mediterranean and East Asia suppress prostate cancer proliferation?

2011 ◽  
Vol 108 (3) ◽  
pp. 424-430 ◽  
Author(s):  
Mu Yao ◽  
Chanlu Xie ◽  
Maryrose Constantine ◽  
Sheng Hua ◽  
Brett D. Hambly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
East Asia ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Prostate Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Prostate Cancer Cells ◽  
The Mediterranean

We have developed a blend of food extracts commonly consumed in the Mediterranean and East Asia, named blueberry punch (BBP), with the ultimate aim to formulate a chemoprevention strategy to inhibit prostate cancer progression in men on active surveillance protocol. We demonstrated previously that BBP inhibited prostate cancer cell proliferation in vitro and in vivo. The purpose of this study was to determine the molecular mechanism responsible for the suppression of prostate cancer cell proliferation by BBP. Treatment of lymph node-metastasised prostate cancer cells (LNCaP) and bone-metastasised prostate cancer cells (PC-3 and MDA-PCa-2b) with BBP (up to 0·8 %) for 72 h increased the percentage of cells at the G0/G1 phase and decreased those at the S and G2/M phases. The finding was supported by the reduction in the percentage of Ki-67-positive cells and of DNA synthesis measured by the incorporation of 5-ethynyl-2′-deoxyuridine. Concomitantly, BBP treatment decreased the protein levels of phosphorylated retinoblastoma, cyclin D1 and E, cyclin-dependent kinase (CDK) 4 and 2, and pre-replication complex (CDC6 and MCM7) in LNCaP and PC-3 cells, whereas CDK inhibitor p27 was elevated in these cell lines. In conclusion, BBP exerts its anti-proliferative effect on prostate cancer cells by modulating the expression and phosphorylation of multiple regulatory proteins essential for cell proliferation.

scholarly journals Inhibitory Effects of (−)-Epigallocatechin-3-gallate on Esophageal Cancer

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 954 ◽  
Author(s):  
Liu-Xiang Wang ◽  
Yun-Long Shi ◽  
Long-Jie Zhang ◽  
Kai-Rong Wang ◽  
Li-Ping Xiang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Dna Methylation ◽  
Cell Proliferation ◽  
Esophageal Cancer ◽  
Synergistic Effect ◽  
Oxidant Stress ◽  
Cancer Cell Proliferation ◽  
Inhibitory Effects ◽  
Epidemiological Evidence ◽  
Metabolic Signaling

There is epidemiological evidence showing that drinking green tea can lower the risk of esophageal cancer (EC). The effect is mainly attributed to tea polyphenols and their most abundant component, (−)-epigallocatechin-3-gallate (EGCG). The possible mechanisms of tumorigenesis inhibition of EGCG include its suppressive effects on cancer cell proliferation, angiogenesis, DNA methylation, metastasis and oxidant stress. EGCG modulates multiple signal transduction and metabolic signaling pathways involving in EC. A synergistic effect was also observed when EGCG was used in combination with other treatment methods.

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