BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer.
BCATc modulates crosstalk between the PI3K/Akt and the Ras/ERK pathway regulating proliferation in triple negative breast cancer.
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DOI：
10.18632/oncotarget.27607
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发表时间：
2020-05-26
期刊：
影响因子：
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通讯作者：
Conway, Myra Elizabeth
中科院分区：
文献类型：
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作者：
Shafei, Mai Ahmed;Forshaw, Thomas;Conway, Myra Elizabeth
已经发现，与正常乳腺组织相比，胞质支链氨基转移酶（BCATc）蛋白在乳腺癌亚型（包括三阴性乳腺癌（TNBC））中高度表达。BCATc对支链氨基酸（BCAA）的催化作用导致谷氨酸和关键代谢物的产生，这些代谢物进一步驱动TCA循环，对细胞代谢和生长至关重要。BCATc的上调与几种恶性肿瘤（包括乳腺癌、神经胶质瘤、卵巢癌和结肠直肠癌）中细胞增殖、细胞周期进展和转移增加相关，但其潜在机制尚不清楚。由于BCAAs（BCATc的底物）的营养水平调节PI 3 K/Akt通路，我们假设BCATc表达增加将通过上调胰岛素/IGF-1信号通路促进肿瘤细胞生长。已知该途径通过激活PI 3 K/Akt和RAS/ERK信号级联增强恶性细胞的增殖和转移。在这里，我们表明BCATc的敲低显著降低了胰岛素和IGF-1介导的TNBC细胞的增殖、迁移和侵袭。对该途径的分析表明，当过表达时，BCATc通过PI 3 K/Akt轴调节增殖，同时减弱Ras/Erk途径，表明BCATc充当这两种途径之间的管道。这最终导致FOXO 3a的增加，FOXO 3a是细胞增殖和Nrf 2的关键调节因子，Nrf 2介导氧化还原稳态。这些数据共同表明，BCATc通过IGF-1/胰岛素PI 3 K/Akt途径调节TNBC细胞增殖、迁移和侵袭，最终导致FOXO 3a和Nrf 2的上调，这为乳腺癌治疗提供了一种新的治疗靶点。
The cytosolic branched chain aminotransferase (BCATc) protein has been found to be highly expressed in breast cancer subtypes, including triple negative breast cancer (TNBC), compared with normal breast tissue. The catabolism of branched-chain amino acids (BCAAs) by BCATc leads to the production of glutamate and key metabolites which further drive the TCA cycle, important for cellular metabolism and growth. Upregulation of BCATc has been associated with increased cell proliferation, cell cycle progression and metastasis in several malignancies including breast, gliomas, ovarian and colorectal cancer but the underlying mechanisms are unclear. As nutrient levels of BCAAs, substrates of BCATc, regulate the PI3K/Akt pathway we hypothesized that increased expression of BCATc would contribute to tumour cell growth through upregulation of the insulin/IGF-1 signalling pathway. This pathway is known to potentiate proliferation and metastasis of malignant cells through the activation of PI3K/Akt and the RAS/ERK signalling cascades. Here we show that knockdown of BCATc significantly reduced insulin and IGF-1-mediated proliferation, migration and invasion of TNBC cells. An analysis of this pathway showed that when overexpressed BCATc regulates proliferation through the PI3K/Akt axis, whilst simultaneously attenuating the Ras/Erk pathway indicating that BCATc acts as a conduit between these two pathways. This ultimately led to an increase in FOXO3a, a key regulator of cell proliferation and Nrf2, which mediates redox homeostasis. Together this data indicates that BCATc regulates TNBC cell proliferation, migration and invasion through the IGF-1/insulin PI3K/Akt pathway, culminating in the upregulation of FOXO3a and Nrf2, pointing to a novel therapeutic target for breast cancer treatment.