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Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma.

Zhang S, Tang W, Weng S, Liu X, Rao B, Gu J, Chen S, Wang Q, Shen X, Xue R, Dong L - Oncotarget (2014)

Bottom Line: Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models.Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models.Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. These authors contributed equally to this work.

ABSTRACT
Patients with esophageal squamous cell carcinoma (ESCC) are often diagnosed with advanced diseases that respond poorly to chemotherapy. Here we reported that Apollon, a membrane-associated inhibitor of apoptosis protein, was overexpressed in ESCC cell lines and clinical ESCC tissues, and Apollon overexpression clinically correlated with poor response to chemotherapy (P = 0.001), and short overall survival (P = 0.021). Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines. Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models. Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models. Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac. Apollon expression strongly and negatively correlated with Smac expression in clinical ESCC tissues (P = 0.001). Apollon targeted Smac for degradation in ESCC cells. The effect of Apollon on chemosensitivity was reversed by Smac knockdown in ESCC cells. Taken together, our data show association of Apollon expression with chemotherapeutic response in ESCC, and provide a strong rationale for combining Apollon antagonism with chemotherapy to treat ESCC.

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Negative correlation between Apollon expression and Smac expression in clinical ESCC samples(A) Typical patterns of Apollon and Smac staining in paired ESCC tissue samples. N, adjacent non-tumorous tissues; T, tumor tissues. Scores of immunochemistry staining of Apollon (B) and Smac (C) in 111 ESCC patients. **P < 0.01. (D) Correlations between Apollon scores and Smac scores in tumor tissues of 111 ESCC patients.
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Figure 2: Negative correlation between Apollon expression and Smac expression in clinical ESCC samples(A) Typical patterns of Apollon and Smac staining in paired ESCC tissue samples. N, adjacent non-tumorous tissues; T, tumor tissues. Scores of immunochemistry staining of Apollon (B) and Smac (C) in 111 ESCC patients. **P < 0.01. (D) Correlations between Apollon scores and Smac scores in tumor tissues of 111 ESCC patients.

Mentions: To further evaluate the role of Apollon in human ESCC, we next examined Apollon expression in tissues from 111 patients with ESCC using immunohistochemistry (IHC) staining. Positive signals of Apollon mainly localized in the cytoplasm. High staining of Apollon could be observed in 62 of 111 (55.8%) cases of ESCCs, whereas in only 12 of 111 (10.8%) cases of adjacent non-tumor tissues. The Apollon scores in tumor tissues were 2.4-fold higher than those in adjacent non-tumor tissues (Fig. 2A and B). Considering the possible relationship between Apollon and Smac, Smac was also stained in the same series of patients. In contrast to Apollon, the Smac scores were 1.8-fold lower in ESCC tumor tissues than in adjacent non-tumor tissues (Fig. 2A and C). Notably, Apollon expression strongly and negatively correlated with Smac expression (R = -0.416, P = 0.001) (Fig. 2D). We further investigated the correlation of Apollon expression with clinicopathologic features. Clinical characteristics of patients are listed in Supplementary Table 1. Clinicopathologic analysis showed that Apollon expression failed to correlate to the clinical pathological factors including TNM stage and tumor differentiation (Supplementary Table 2). To give a comprehensive evaluation of IAPs expression in human ESCC, we detected other members of IAPs by IHC staining in 111 patients with ESCC. We found that c-IAP1 (Birc2), XIAP (Birc4), Survivin (Birc5) and Livin (Birc7) were overexpressed in ESCC tissues, while NAIP (Birc1) and c-IAP2 (Birc3) were comparable between tumor tissues and adjacent non-tumor tissues (Supplementary Fig. 2).


Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma.

Zhang S, Tang W, Weng S, Liu X, Rao B, Gu J, Chen S, Wang Q, Shen X, Xue R, Dong L - Oncotarget (2014)

Negative correlation between Apollon expression and Smac expression in clinical ESCC samples(A) Typical patterns of Apollon and Smac staining in paired ESCC tissue samples. N, adjacent non-tumorous tissues; T, tumor tissues. Scores of immunochemistry staining of Apollon (B) and Smac (C) in 111 ESCC patients. **P < 0.01. (D) Correlations between Apollon scores and Smac scores in tumor tissues of 111 ESCC patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196194&req=5

Figure 2: Negative correlation between Apollon expression and Smac expression in clinical ESCC samples(A) Typical patterns of Apollon and Smac staining in paired ESCC tissue samples. N, adjacent non-tumorous tissues; T, tumor tissues. Scores of immunochemistry staining of Apollon (B) and Smac (C) in 111 ESCC patients. **P < 0.01. (D) Correlations between Apollon scores and Smac scores in tumor tissues of 111 ESCC patients.
Mentions: To further evaluate the role of Apollon in human ESCC, we next examined Apollon expression in tissues from 111 patients with ESCC using immunohistochemistry (IHC) staining. Positive signals of Apollon mainly localized in the cytoplasm. High staining of Apollon could be observed in 62 of 111 (55.8%) cases of ESCCs, whereas in only 12 of 111 (10.8%) cases of adjacent non-tumor tissues. The Apollon scores in tumor tissues were 2.4-fold higher than those in adjacent non-tumor tissues (Fig. 2A and B). Considering the possible relationship between Apollon and Smac, Smac was also stained in the same series of patients. In contrast to Apollon, the Smac scores were 1.8-fold lower in ESCC tumor tissues than in adjacent non-tumor tissues (Fig. 2A and C). Notably, Apollon expression strongly and negatively correlated with Smac expression (R = -0.416, P = 0.001) (Fig. 2D). We further investigated the correlation of Apollon expression with clinicopathologic features. Clinical characteristics of patients are listed in Supplementary Table 1. Clinicopathologic analysis showed that Apollon expression failed to correlate to the clinical pathological factors including TNM stage and tumor differentiation (Supplementary Table 2). To give a comprehensive evaluation of IAPs expression in human ESCC, we detected other members of IAPs by IHC staining in 111 patients with ESCC. We found that c-IAP1 (Birc2), XIAP (Birc4), Survivin (Birc5) and Livin (Birc7) were overexpressed in ESCC tissues, while NAIP (Birc1) and c-IAP2 (Birc3) were comparable between tumor tissues and adjacent non-tumor tissues (Supplementary Fig. 2).

Bottom Line: Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models.Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models.Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. These authors contributed equally to this work.

ABSTRACT
Patients with esophageal squamous cell carcinoma (ESCC) are often diagnosed with advanced diseases that respond poorly to chemotherapy. Here we reported that Apollon, a membrane-associated inhibitor of apoptosis protein, was overexpressed in ESCC cell lines and clinical ESCC tissues, and Apollon overexpression clinically correlated with poor response to chemotherapy (P = 0.001), and short overall survival (P = 0.021). Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines. Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models. Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models. Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac. Apollon expression strongly and negatively correlated with Smac expression in clinical ESCC tissues (P = 0.001). Apollon targeted Smac for degradation in ESCC cells. The effect of Apollon on chemosensitivity was reversed by Smac knockdown in ESCC cells. Taken together, our data show association of Apollon expression with chemotherapeutic response in ESCC, and provide a strong rationale for combining Apollon antagonism with chemotherapy to treat ESCC.

Show MeSH
Related in: MedlinePlus