Banno Asoka, Garcia Daniel A, van Baarsel Eric D, Metz Patrick J, Fisch Kathleen, Widjaja Christella E, Kim Stephanie H, Lopez Justine, Chang Aaron N, Geurink Paul P, Florea Bogdan I, Overkleeft Hermen S, Ovaa Huib, Bui Jack D, Yang Jing, Chang John T
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Oncotarget. 2016 Apr 19;7(16):21527-41. doi: 10.18632/oncotarget.7596.
The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.
上皮-间质转化（EMT）赋予癌细胞表型可塑性，这有助于癌症干细胞（CSCs）的形成，并推动转移级联反应。虽然有大量证据支持EMT在驱动癌细胞扩散中的作用，但对于通过EMT调控CSCs形成的细胞内分子机制却知之甚少。在此，我们发现永生化人乳腺上皮细胞在EMT过程中β2和β5蛋白酶体亚基活性下调。此外，选择性蛋白酶体抑制使乳腺上皮细胞获得某些类似于癌症干细胞的形态和功能特征，包括CD44表达、自我更新和肿瘤形成。转录组分析表明，蛋白酶体抑制的细胞部分通过调节TGF-β信号通路，与经历过EMT的细胞共享基因表达特征。这些发现表明，乳腺上皮细胞中蛋白酶体活性的选择性下调可启动EMT程序并获得癌症干细胞样表型。随着蛋白酶体抑制剂在癌症治疗中的应用越来越广泛，我们的研究结果凸显了这些治疗策略的潜在风险，并提示了癌细胞可能逃避基于蛋白酶体抑制剂治疗的一种可能机制。
