Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis

Abstract

Src plays an important role in cell proliferation, differentiation, adhesion, and migration. Altered Src activity has been strongly implicated in the development, growth, progression, and metastasis of human cancers. We have analysed the change and regulation of Src upon cell detachment in anoikis-resistant human lung adenocarcinoma cells and compared with that of relatively normal and anoikis-sensitive epithelial cells. We found that Src activity was increased in the anoikis-resistant lung tumor cells when they were detached and cultured in suspension. The detachment-induced Src activation in the tumor cells compensates for the loss of cell survival signals caused by disruption of cell-matrix interactions and contributes to anoikis resistance of the tumor cells. Pyk2, rather than PI 3K/Akt or Erk, appears to be the key downstream effecter of Src in mediating the cell survival signals. The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. The increased Src activity upon cell detachment may contribute to the metastasis potential of malignant tumors.

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors

“…2 Several research groups, including us, have reported that Src, a non-receptor type tyrosine kinase, has a role in the anoikis resistance in lung adenocarcinomas. [3][4][5] We have demonstrated that 1) intralymphatic floating lung adenocarcinoma cells observed in primary tumor tissues form compact nests expressing E-cadherin and phosphorylated Src; 2) these two proteins are also expressed in tumor spheroids of four lung adenocarcinoma cell lines (LC-KJ, HCC827, H1650, and H1975) cultured in suspension, the shape of which is similar to intralymphatic tumor cell nests observed in tissues. 5 We thus consider tumor spheroids of the four cell lines in suspension culture system to be a suitable in vitro model of circulating tumor cells.…”

Essential role of Pyk2 and Src kinase activation in neuropeptide-induced proliferation of small cell lung cancer cells

“…Downregulation of Pyk2 expression by RNAi attenuated neuropeptide-mediated Src kinase phosphorylation while pharmacological inhibition of Src kinases resulted in diminished Pyk2 phosphorylation. It is well established that Pyk2 and Src kinases act in concert to mediate downstream effects in different cellular settings (Blaukat et al, 1999;Wei et al, 2004). However, the two tyrosine kinases cannot be placed in a definitive sequential order.…”

Anoikis: an emerging hallmark in health and diseases

“…Giannoni et al [48] observed that in cancer cells the oxidative intracellular milieu strongly correlates with induction of anoikis resistance; ROS production protects tumour cells from anoikis through the oxidation/activation of the tyrosine kinase Src, thus granting the activation of pro-survival pathways through a Src-dependent and ligand-independent phosphorylation of EGFR, which leads to Bim degradation. Furthermore, in human lung adenocarcinoma cells, Src activation compensates for the loss of cell-survival signals caused by disruption of cell-ECM interactions and contributes to anoikis resistance [92]. A redox-mediated activation of Src has been recently evidentiated also in several different tumour types over-expressing angiopoietin-like 4 protein (ANGPTL4).…”