Activation of the PI3K/Akt pathway and chemotherapeutic resistance

West, Kip A.; Castillo, S. Sianna; Dennis, Phillip A.

doi:10.1016/s1368-7646(02)00120-6

Cited by 535 publications

(480 citation statements)

References 110 publications

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“…There has been increasing evidence that AKT is activated in many different cancer types and that this signalling pathway confers a potent survival signal that relates to chemo-and radioresistance (Brognard et al, 2001;West et al, 2002). Furthermore, early studies have demonstrated that inhibition of AKT sensitises tumours to the apoptotic effect of both chemo-and radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…AKT has been recently demonstrated to be a major mediator of survival signals in a variety of cells, including cancer cells (Tang et al, 2001;Vivanco and Sawyers, 2002). Constitutive activation of AKT provides a potent antiapoptotic signal in cancer cells conferring chemo-and radioresistance (Brognard et al, 2001;West et al, 2002). To date, there have been a few studies on the incidence of AKT activation in various tumours using archived pathologic specimens (Dhawan et al, 2002;Gupta et al, 2002;Itoh et al, 2002;Malik et al, 2002;Perez-Tenorio and Stal, 2002).…”

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confidence: 99%

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Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

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When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P ¼ 0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P ¼ 0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Incidence, mechanism and prognostic value of activated AKT in pancreas cancer

et al. 2003

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“…6A-D). Akt is a cytosolic signal transduction protein kinase that plays an important role in cell survival pathways (West et al 2002). Induction of Akt activity is primarily dependent on the PI3 K pathway.…”

Section: Bufalin Reduces the Receptor Phosphorylation And/or Protein mentioning

confidence: 99%

“…Induction of Akt activity is primarily dependent on the PI3 K pathway. Akt can be activated by many forms of cellular stress, such as those observed under treatment with anticancer agents (West et al 2002). Once activation, Akt controls cellular functions such as apoptosis, cell cycle, gene transcription, and protein synthesis through the phosphorylation of downstream substrates such as NF-jB, p53 and COX-2 (West et al 2002).…”

Section: Bufalin Reduces the Receptor Phosphorylation And/or Protein mentioning

confidence: 99%

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

et al. 2010

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Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non-small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time-and dosedependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-jB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/cMet-Akt/p44/42/p38-NF-jB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.

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“…Since high concentrations of wortmannin inhibit myosin light chain kinase (MLCK) in other organisms, 14 we assayed macronuclear acidification and nuclear overproliferation in cells treated with the highly specific MLCK inhibitor ML-7. ML-7 (1-10 mM) had no effect on nuclear acidification or proliferation ( Figure 1b).…”

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confidence: 99%