PI3K and ERK-Induced Rac1 Activation Mediates Hypoxia-Induced HIF-1α Expression in MCF-7 Breast Cancer Cells

Du, Jie; Xu, Rui; Hu, Zhenzhen; Tian, Ye; Zhu, Yichao; Gu, Luo; Zhou, Lei

doi:10.1371/journal.pone.0025213

Cited by 94 publications

(84 citation statements)

References 57 publications

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“…S3A). Activation of the MAPK/ERK and Akt/mTOR pathways has been reported to enhance HIF-1α protein synthesis [6, 7]. We also observed that IMQ treatment promoted the phosphorylation of ERK1/2 and Akt in BCC and SCC12 cells, indicating that the MAPK/ERK and Akt/mTOR signaling pathways were activated (Fig.…”

Section: Resultssupporting

confidence: 72%

Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells

Huang

Kao

et al. 2014

Oncotarget

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Tumor cells rely on aerobic glycolysis to maintain unconstrained cell growth and proliferation. Imiquimod (IMQ), a synthetic Toll-like receptor (TLR) 7/8 ligand, exerts anti-tumor effects directly by inducing cell death in cancer cells and/or indirectly by activating cellular immune responses against tumor cells. However, whether IMQ modulates glucose metabolism pathways remains unclear. In this study, we demonstrated that IMQ can enhance aerobic glycolysis by up-regulating HIF-1α expression at the transcriptional and translational levels via ROS mediated STAT3- and Akt-dependent pathways, independent of TLR7/8 signaling. The genetic silencing of HIF-1α not only repressed IMQ-induced aerobic glycolysis but also sensitized cells to IMQ-induced apoptosis due to faster ATP and Mcl-1 depletion. Moreover, the glucose analog 2-DG and the Hsp90 inhibitor 17-AAG, which destabilizes the HIF-1α protein, synergized with IMQ to induce tumor cell apoptosis in vitro and significantly inhibited tumor growth in vivo. Thus, we hypothesize that the IMQ-induced up-regulation of HIF-1α and aerobic glycolysis is a protective response to the metabolic stress generated by IMQ treatment, and thus, co-treatment with inhibitors of HIF-1α and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumor effects of IMQ in clinical settings.

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Section: Resultssupporting

confidence: 72%

Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells

Huang

Kao

et al. 2014

Oncotarget

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“…Hu et al (18) demonstrated that EGF stimulates migration of hepatoma cell line HepG2 through GEP100-dependent activation of the Arf6/ERK/Rac1 signaling pathway. Du et al (16) reported that the PI3K and ERK-induced Rac1 activation is required for hypoxia-induced HIF-1α expression in breast cancer cells. Jones et al (15) proposed that the association of PLC-γ1 with complexes containing GIT1 and β-Pix is essential for its role in integrin-mediated cell spreading and motility, during which the activation of Cdc42 and Rac1, which are downstream of PLC-γ1, is crucial since depletion of Cdc42 or Rac1 abolishes the elongated cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of Rac1 at Ser71 has been reported to modulate downstream signaling by inhibiting the interaction of Rac1 with its effectors (12). In addition, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and phospholipase C γ1 (PLCγ1) -mediated signal transduction have been implicated in the Rac1 signaling pathway in various human cancer cell lines (15)(16)(17)(18). Therefore, the current study also aimed to establish the effects of inhibiting these pathways on Rac1 activation, and the ability of PKG II to directly phosphorylate Rac1.…”

Section: Introductionmentioning

confidence: 99%

Type II cyclic guanosine monophosphate-dependent protein kinase inhibits Rac1 activation in gastric cancer cells

Wang

Chen

et al. 2015

Oncology Letters

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Abstract. Enhanced motility of cancer cells is a critical step in promoting tumor metastasis, which remains the major cause of gastric cancer-associated mortality. The small GTPase Rac1 is a key signaling component in the regulation of cell migration. Previous studies have demonstrated that Rac1 activity may be regulated by protein kinase G (PKG); however, the underlying mechanism is not yet clear. The current study aimed to investigate the effect of type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) on Rac1 activity. The human gastric cancer cell line AGS was infected with adenoviral constructs encoding PKG II to increase the expression of this enzyme, and treated with a cGMP analog (8-pCPT-cGMP) to induce its activation. A Transwell assay was employed to measure cell migration, and the activity of Rac1 was assessed using a pull-down assay. Immunoprecipitation was used to isolate the Rac1 protein. Phosphorylation of phosphatidylinositol 4,5 bisphosphate 3 kinase (PI3K) and its downstream effecter protein kinase B (Akt) are associated with lysophosphatidic acid (LPA)-induced motility/migration of cancer cells. Extracellular signal regulated kinase (ERK) is the major signaling molecule of the Mitogen activated protein kinase (MAPK) mediated signaling pathway. ERK and its upstream activator MAPK kinase (MEK) are also involved in LPA-induced motility/migration of cancer cells. Phosphorylation of PI3K/Akt, MEK/ERK and enriched Rac1 were detected by western blotting. The results revealed that blocking the activation of Rac1 by ectopically expressing an inactive Rac1 mutant (T17N) impeded LPA-induced cell migration. Increased PKG II activity inhibited LPA-induced migration and LPA-induced activation of Rac1; however, it had no effect on the phosphorylation of Rac1. PKG II also inhibited the activation of PI3K/Akt and MEK/ERK mediated signaling, which is important for LPA-induced Rac1 activation. These results suggest that PKG II affects LPA-stimulated migration of AGS cells by blocking Rac1 activation, via inhibition of PI3K/Akt and MEK/ERK mediated signaling.

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“…In other studies, NF-B and HIF-1␣ are shown to be the downstream targets of PI3K/Akt and/or ERK (22)(23)(24). Thus, to investigate the role of these signaling nodes in gemcitabine-induced activation of NF-B and HIF-1␣, we treated the PC cells with specific pharmacological inhibitors of Akt (LY294002) and ERK (PD98059) prior to stimulation with gemcitabine.…”

Section: Activation Of Nf-b and Hif-1␣ Involves Ros-mediated Activatimentioning

confidence: 99%

An Undesired Effect of Chemotherapy

Arora

Bhardwaj

Singh

et al. 2013

Journal of Biological Chemistry

147

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Background: CXCR4 signaling protects pancreatic cancer cells from gemcitabine toxicity. However, the effect of gemcitabine on this resistance mechanism is unclear. Results: Gemcitabine up-regulates CXCR4 expression in pancreatic cancer cells and promotes their invasiveness. Conclusion: CXCR4 signaling serves as a counterdefense mechanism against gemcitabine. Significance: These findings are significant for the formulation of effective therapeutic strategies against pancreatic cancer.

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PI3K and ERK-Induced Rac1 Activation Mediates Hypoxia-Induced HIF-1α Expression in MCF-7 Breast Cancer Cells

Cited by 94 publications

References 57 publications

Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells

Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells

Type II cyclic guanosine monophosphate-dependent protein kinase inhibits Rac1 activation in gastric cancer cells

An Undesired Effect of Chemotherapy

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