Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling
Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling
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DOI：
10.1073/pnas.1217072110
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发表时间：
2013-03-12
影响因子：
11.1
通讯作者：
Bentires-Alj, Mohamed
中科院分区：
文献类型：
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作者：
Britschgi, Adrian;Bill, Anke;Bentires-Alj, Mohamed
钙激活氯离子通道Anoctamin 1(ANO1)位于11q13扩增子内，是人类癌症中最常被扩增的染色体区域之一，但其在肿瘤发生中的作用尚不清楚。11q13区域的扩增与15%的乳腺癌相似。ANO1是否在乳腺肿瘤中被扩增，基因扩增在多大程度上促进了ANO1的过度表达，以及ANO1的过度表达是否对肿瘤的维持至关重要，目前尚不清楚。我们发现，ANO1在乳腺癌细胞系和原发肿瘤中被扩增并高表达。ANO1基因扩增与疾病分级和预后不良相关。在ANO1扩增的乳腺癌细胞系和其他携带11q13扩增的癌症中敲除ANO1可抑制已建立的肿瘤异种移植瘤的增殖、诱导凋亡和减少肿瘤生长。此外，ANO1氯通道活性对细胞活力也很重要。从机制上讲，ANO1基因敲除或药物抑制其氯通道活性会减少EGF受体(EGFR)和钙调蛋白依赖的蛋白激酶II(CaMKII)信号，从而在体内外减弱AKT、v-src肉瘤病毒癌基因同源(SRC)和细胞外信号调节激酶(ERK)的激活。我们的结果强调了ANO1氯通道参与肿瘤进展，并通过11q13扩增为人类癌症的致癌信号提供了洞察力，从而确立了ANO1作为治疗这些高度流行的肿瘤类型的有希望的靶点。
The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified In similar to 15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.