Bcl‐X_L and STAT3 mediate malignant actions of γ‐irradiation in lung cancer cells

Abstract

Previous reports suggest that, in addition to its therapeutic effects, ionizing radiation (IR) increases the invasiveness of surviving cancer cells. Here, we demonstrate that this activity of IR in lung cancer cells is mediated by a signaling pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and matrix metalloproteinase (MMP-2). The invasion-promoting doses of IR also increased and reduced the levels of vimentin and E-cadherin, respectively, both of which are markers for the epithelial-mesenchymal transition (EMT). Interestingly, all of these malignant actions of IR were mimicked by the overexpression of Bcl-X L , a pro-survival member of the Bcl-2 family, in lung cancer cells. Moreover, both RNA and protein levels of Bcl-X L were elevated upon irradiation of the cells, and the prevention of this event using small-interfering RNAs of Bcl-X L reduced the ability of IR to promote invasion signals and EMT-associated events. This suggests that Bcl-X L functions as a signaling mediator of the malignant effects of IR. It was also demonstrated that IR enhances signal transducer and activator of transcription 3 (STAT3) phosphorylation, and the reduction of STAT3 levels via RNA interference prevented IR-induced Bcl-X L accumulation, and thus all the tested Bcl-X L -dependent events. Overall, the data suggest that IR induces Bcl-X L accumulation via STAT3, which then promotes cancer cell invasion and EMT-associated markers. Our findings demonstrate a novel function of Bcl-X L in cancer, and also advance our understanding of the malignant actions of IR significantly. (Cancer Sci 2010; 101: 1417-1423 A lthough ionizing radiation (IR) is widely utilized for cancer therapy, (1)(2)(3) recent studies have shown that IR also exerts undesirable effects on cancer cells. For example, the irradiation of various types of cancer cells, including glioma, (4) hepatocellular carcinoma, (5) pancreatic cancer, (6) and meningioma cells, (7) with sublethal doses of IR resulted in an increase in their invasiveness in culture. Moreover, a large number of studies using animal models have demonstrated that local radiotherapy administered to primary tumors speeds their metastatic growth in vivo, (8)(9)(10) thereby suggesting that besides its therapeutic effects, IR promotes the malignant behaviors of surviving cancer cells. This latter effect of IR is also consistent with the finding that local failure after radiotherapy increases the probability that distant metastasis will develop in cancer patients. (11) Therefore, preventing such undesirable action of IR may be an essential component of efforts to improve the efficacy of radiotherapy.In order to develop a strategy toward this objective, the mechanism by which IR promotes cancer cell invasion should be delineated. Previous studies using glioma cells have suggested that IR stimulates signaling components, such as p38 kinase, phosphoinositide 3-kinase (PI3K), and Akt, leading to matrix metalloproteinase-2 (MMP-2) expression and thus enhanced cell invasion.(4) The ability of IR to ind...

Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer‐derived CD133‐positive cells

“…Indeed, these data were consistent with a recent report that IR enhances the invasiveness of and the events related to the epithelial-mesenchymal transition of lung cancer cells by Bcl-xL accumulation through STAT3, suggesting that STAT3 and Bcl-xL may contribute to the malignancy of lung cancer cells. 34 Notably, in vivo xenotransplanted analysis indicated that cucurbitacin I may be a sensitizer that synergistically enhances both radiosensitivity and chemosensitivity in a xenotransplanted model of human lung CSCs (Fig. 6).…”

The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins

“…To our knowledge, this is the first report demonstrating that the prosurvival Bcl-2 proteins are direct targets of the p53/p21 complex. In addition to cell invasion and death, prosurvival Bcl-2 proteins can regulate various other cellular functions, including autophagy (24)(25)(26)(27), senescence (28)(29)(30), and the epithelial-mesenchymal transition (31)(32)(33)(34). Notably, these cellular functions are also regulated by p53 and p21 (1,2,30,(35)(36)(37)(38)(39).…”

Let-7c Governs the Acquisition of Chemo- or Radioresistance and Epithelial-to-Mesenchymal Transition Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma

“…Overexpression of Bcl-xL has been found to increase the phosphorylation levels of Akt protein in lung cancer cells (18). In other researches, it was also shown that AKT activation caused EMT characterized by downregulation of numerous epithelial cell-specific proteins (17).…”