Abstract
BackgroundIn a previous analysis using a lung cancer cell line model, we have found that therapies directed against secreted clusterin (sCLU) and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro. Here, we investigated the therapies directed against sCLU on the DDP-based chemotherapy in vivo and explored the mechanism.MethodsUsing lung cancer cell lines, A549 cells and DDP-resistant A549 cells (A549DDP), we determined the effect of sCLU silencing using short interfering double-stranded RNA (siRNA) on chemosensitivity in immunocompromised mice bearing A549DDP tumors. We then determined the effect of sCLU overexpression via stable sCLU transfection on chemosensitivity in immunocompromised mice bearing A549 tumors. The effect of sCLU silencing or overexpression on pAkt and pERK1/2 expression and chemosensitivity in vivo was detected by Western blot assay.ResultsThe results showed sCLU silencing increased the chemosensitivity of A549DDP cells to DDP in vivo via downregulation of pAkt and pERK1/2 expression. And sCLU overexpression decreased the chemosensitivity of A549 cells to DDP in vivo via upregulation of pAkt and pERK1/2 expression.ConclusionsWe therefore concluded that the DDP-induced sCLU activation, which involved induction of pAkt and pERK1/2 activation that confer DDP resistance in immunocompromised mice and alteration of this balance, allows sensitization to the antitumor activity of cisplatin chemotherapy.
Highlights
In a previous analysis using a lung cancer cell line model, we have found that therapies directed against secreted clusterin and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro
Clusterin overexpression in vivo significantly increased the resistance of the lung cancer cells to cisplatin Based on the in vitro experiment of clusterin in the cisplatin resistance of lung cancers [11], we further examined if clusterin expression affects the cisplatin sensitivity in vivo; A549, A549/secreted clusterin (sCLU), and A549/pcDNA3.1 cells were injected subcutaneously into the right flank of nude mice
Cisplatin could significantly inhibit the tumor growth in mice injected with A549/pCDNA3.1 scramble cells and A549 cells compared to the mice injected with A549/sCLU cells (Figure 1A)
Summary
In a previous analysis using a lung cancer cell line model, we have found that therapies directed against secreted clusterin (sCLU) and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro. Methods: Using lung cancer cell lines, A549 cells and DDP-resistant A549 cells (A549DDP), we determined the effect of sCLU silencing using short interfering double-stranded RNA (siRNA) on chemosensitivity in immunocompromised mice bearing A549DDP tumors. The effect of sCLU silencing or overexpression on pAkt and pERK1/2 expression and chemosensitivity in vivo was detected by Western blot assay. Results: The results showed sCLU silencing increased the chemosensitivity of A549DDP cells to DDP in vivo via downregulation of pAkt and pERK1/2 expression. SCLU overexpression decreased the chemosensitivity of A549 cells to DDP in vivo via upregulation of pAkt and pERK1/2 expression.
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