Site-specific activation of AKT protects cells from death induced by glucose deprivation

Gao, Meng; Liang, Jiyong; Lu, Yiling; Guo, Haipeng; Germán, Péter; Bai, Shanshan; Jonasch, Eric; Yang, Xinggang; Mills, Gordon B.; Ding, Zhiyong

doi:10.1038/onc.2013.2

Cited by 54 publications

(47 citation statements)

References 48 publications

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“…To futher test this hypothesis, we tested the effect of glucose starvation, a strategy that disrupt glycolysis, on p-Akt in Si-C and Si-PKM cells. Consistence with previous studies, glucose starvation for 2 hours led to up-regulation of p-Akt in Si-C cells [4]. However, p-Akt in Si-PKM cells stayed unchanged in response to glucose starvation (Figure 3C and D), indicating that Si-PKM cells are already in a state that mimics glycolysis disruption.…”

Section: Resultssupporting

confidence: 89%

Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown

Qin

Chen

et al. 2014

Cell Biosci

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BackgroundPKM2 is an attractive target for cancer therapy, however, for many cancer cells, PKM2 knockdown only leads to a modest impairment of survival and proliferation. It is not known whether PKM2 knockdown rewires cell signaling pathways in these “PKM2 knockdown resistant” cells, and whether the rewired pathways are needed for their survival.FindingsIn present study, we investigated the effects of PKM2 knockdown on cellular signaling pathways in “PKM2 knockdown resistant” cancer cells. We found that knockdown of PKM2 leads to activation of Akt. Furthermore, we revealed that activation of Akt in PKM2 knockdown cells is a result of glycolysis disruption. Inhibiton of PI3K-Akt signaling pathway leads to significant growth inhibition and apoptosis in PKM2 knockdown cells.ConclusionsOverall, our results indicate that activation of Akt is necessary for the survival of PKM2 knockdown cells. Combing PKM2 knockdown with PI3K or Akt inhibitors may lead to a better chance to kill tumors. Our research may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant Akt signaling.

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Section: Resultssupporting

confidence: 89%

Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown

Qin

Chen

et al. 2014

Cell Biosci

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“…Serine/threonine kinase Akt, also known as Protein Kinase B (PKB), has emerged as a central node in diverse cellular processes including cell survival, proliferation, metabolism, apoptosis, angiogenesis and migration [34,35,36]. Akt was reported aberrantly overexpressed in PANC-1 and other human pancreatic cancer cell lines, and a high expression of Akt was found associated with their remarkable tolerance for nutrient starvation [37,38].…”

Section: Discussionmentioning

confidence: 99%

Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress

Wang²,

Chen³

et al. 2015

Cell Physiol Biochem

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Background: Aberrant expression of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress. Methods: Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress. Results: NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking. Conclusions: These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress.

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“…Multiple other mechanisms of AKT activation or inhibition have been identified in RCC, contributing to aberrant PI3K/AKT pathway activation. We have shown that glucose deprivation induces a unique form of AKT phosphorylation and activation in multiple cell lines, including 786-0, RXF393, ACHN, and other RCC cells (Gao et al, 2014). AKT is selectively phosphorylated on Thr308 through enhanced protein complex formation with PDK1 and 78-kDa glucose-regulated protein under glucose-deprivation conditions, which likely represents a novel AKT activation mechanism in RCC, as well as in other cancers when metabolic stress is present (Dawood et al, 2014; Gao et al, 2014).…”

Section: Additional Mechanisms Activating the Pi3k/akt Pathway In Rccmentioning

confidence: 99%

The PI3K/AKT Pathway and Renal Cell Carcinoma

Guo

Germán

Bai

et al. 2015

Journal of Genetics and Genomics

262

195

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The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarizes the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.

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Site-specific activation of AKT protects cells from death induced by glucose deprivation

Cited by 54 publications

References 48 publications

Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown

Activation of Akt protects cancer cells from growth inhibition induced by PKM2 knockdown

Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress

The PI3K/AKT Pathway and Renal Cell Carcinoma

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