Abstract
BackgroundPolymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. Conceivably, drugs that target such polyFN may fight against cancer metastasis. While stilbene analogs trigger pro-apoptotic effect on attached cancer cells, whether they prevent polyFN assembly and metastasis of suspended cancer cells via an apoptosis-independent manner remains unexplored.MethodsWe depleted suspended Lewis lung carcinoma (LLC) cells of polyFN by silencing the endogenous FN expression or pterostilbene (PS) to examine whether metastasis of lung cancer cells could thus be suppressed. We investigated whether PS regulates AKT-ERK signaling axis to suppress polyFN assembly in suspended LLC cells independently of apoptosis. We tested the therapeutic effects of orally administered PS against cancer metastasis.ResultsBoth FN-silencing and PS among the three stilbenoids indeed significantly reduced polyFN assembly and lung metastasis of suspended LLC cells in an apoptosis-independent manner. Mechanistically, PS-induced AKT phosphorylation (pAKT) and suppressed ERK phosphorylation (pERK) in suspended LLC cells, whereas pretreatment with a PI3K inhibitor, LY294002, effectively reduced pAKT, rescued pERK, and consequently reversed the PS-suppressed polyFN assembly on LLC cells; these pretreatment effects were then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was further overruled with U0126. Finally, we found that PS, when orally administered in experimental metastasis assays, both significantly prevented lung colonization and metastasis of LLC cells and reduced the already established tumor growth in the mouse lungs.ConclusionsPS suppressed AKT/ERK-regulated polyFN assembly on suspended LLC cells and pulmonary metastasis. PS possesses potency in both preventing and treating lung metastasis of lung cancer cells in apoptosis-independent and apoptosis-dependent manners, respectively.
Highlights
Polymeric fibronectin assembled on suspended breast cancer cells is required for metastasis
PolyFN assembly on suspended Lewis lung carcinoma (LLC) cells is required for pulmonary metastasis We employed small hairpin RNA (shRNA)-mediated FN gene silencing to investigate how endogenous FN expression contributes to the Polymeric fibronectin (polyFN) assembly on suspended lung cancer cells
Since covalently cross linkage in addition to disulfide bond occurs during the maturation of polyFN [10], that FN shRNAs treatments significantly decreased polyFN in suspended LLC cells under reducing conditions as represented by FN on GT (Fig. 1a, b) suggested the requirement of endogenous FN expression for FN polymerization during matrix assembly
Summary
Polymeric fibronectin (polyFN) assembled on suspended breast cancer cells is required for metastasis. The outcomes of these therapeutic strategies often ironically lead to increased mortality due either to the subsequent drug resistance and to metastatic recurrence or tumor cell dissemination within the circulation upon surgical removal of tumor tissues [4]. This issue has put scientists in a dilemma and has drawn worldwide attention. In complement with both primary tumor-targeted cytotoxic approaches and surgical strategies, effective inhibition of metastases by means of post-operational measures against circulating tumor cells (CTCs), even including those that are insensitive to cytotoxic therapies, may alternatively be an ideal anti-cancer adjuvant strategy [5, 6]. Not enough attention has been devoted to developing this therapeutic modality against lung cancer
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