Heterogeneity of neuroblastoma cell lines in insulin-like growth factor 1 receptor/Akt pathway-mediated cell proliferative responses.
Heterogeneity of neuroblastoma cell lines in insulin-like growth factor 1 receptor/Akt pathway-mediated cell proliferative responses.
复制标题
神经母细胞瘤细胞系在胰岛素样生长因子 1 受体/Akt 通路介导的细胞增殖反应中的异质性。
DOI：
10.1111/cas.12204
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发表时间：
2013
期刊：
影响因子：
5.7
通讯作者：
Komada Y
中科院分区：
文献类型：
--
作者：
Qi L;Toyoda H;Shankar V;Sakurai N;Amano K;Kihira K;Iwasa T;Deguchi T;Hori H;Azuma E;Gabazza EC;Komada Y
胰岛素样生长因子1受体（IGF-1 R）对癌细胞增殖至关重要;然而，最近的临床抗IGF-1 R试验并未显示出明确的癌症治疗临床获益。我们假设IGF-1 R信号介导的增殖反应在神经母细胞瘤（NB）细胞中是异质性的，并分析了在三种不同培养基中培养的31个NB细胞系的细胞生长，包括Hybrid SFM培养基（含胰岛素）和RPMI 1640（含/不含10% FBS）。结果显示，IGF和胰岛素可诱导13株细胞增殖和Akt磷酸化，并可被Akt抑制剂MK 2206和IGF-1 R抑制剂苦鬼臼脂素抑制。有趣的是，这13个细胞系中有3个在RPMI 1640中显示Akt自磷酸化和细胞增殖;它们的增殖被抗IGF-1或抗IGF-2中和抗体下调，表明IGF-1 R/Akt通路中存在自分泌环。18 NB细胞系没有增殖RPMI 1640，即使Akt磷酸化上调IGF和胰岛素。根据IGF-1 R/Akt通路的异质性反应，31个NB细胞系可分为第1组（自分泌IGF-介导）、第2组（外源IGF-介导）和第3组（部分外源IGF-介导）NB细胞系。此外，第3组NB细胞系在血清饥饿诱导的caspase 3裂解和苦鬼臼脂素诱导的G2/M期阻滞方面与第1组和第2组不同。这些结果表明，IGF-1 R/Akt通路的反应是NB对IGF-1 R拮抗剂敏感性的重要决定因素。据我们所知，这是第一份描述IGF-1 R/Akt-介导的NB细胞增殖异质性的报告。
Insulin‐like growth factor 1 receptor (IGF‐1R) is critical for cancer cell proliferation; however, recent clinical anti‐IGF‐1R trials did not show clear clinical benefit in cancer therapy. We hypothesized that IGF‐1R signaling‐mediated proliferative response is heterogeneous in neuroblastoma (NB) cells, and analyzed the cell growth of 31 NB cell lines cultured in three different media, including Hybridoma‐SFM medium (with insulin) and RPMI1640 with/without 10% FBS. Three growth patterns were found. In response to IGF and insulin, cell proliferation and Akt phosphorylation were upregulated in 13 cell lines, and suppressed by MK2206 (Akt inhibitor) and picropodophyllin (IGF‐1R inhibitor). Interestingly, 3 of these 13 cell lines showed Akt self‐phosphorylation and cell proliferation in RPMI1640; their proliferation was downregulated by anti‐IGF‐1 or anti‐IGF‐2 neutralizing antibody, suggesting the existence of an autocrine loop in the IGF‐1R/Akt pathway. Eighteen NB cell lines did not proliferate in RPMI1640, even though Akt phosphorylation was upregulated by IGF and insulin. Based on the heterogeneous response of the IGF‐1R/Akt pathway, the 31 NB cell lines could be classified into group 1 (autocrine IGF‐mediated), group 2 (exogenous IGF‐mediated) and group 3 (partially exogenous IGF‐mediated) NB cell lines. In addition, group 3 NB cell lines were different from group 1 and 2, in terms of serum starvation‐induced caspase 3 cleavage and picropodophyllin‐induced G2/M arrest. These results indicate that the response of the IGF‐1R/Akt pathway is an important determinant of the sensitivity to IGF‐1R antagonists in NB. To our knowledge, this is the first report describing heterogeneity in the IGF‐1R/Akt‐mediated proliferation of NB cells.