Tat-hspb1 Suppresses Clear Cell Renal Cell Carcinoma (ccRCC) Growth via Lysosomal Membrane Permeabilization.
Tat-hspb1 Suppresses Clear Cell Renal Cell Carcinoma (ccRCC) Growth via Lysosomal Membrane Permeabilization.
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本研究通过对人肾透明细胞癌及癌旁正常组织的肽组分析，发现了一种新的来源于HSPB 1蛋白的内源性肽。我们通过将这种HSPB 1衍生肽与HIV-Tat缀合产生了一种新的肽，命名为Tat-hspb 1。我们发现Tat-hspb 1可以抑制ccRCC细胞的增殖和迁移。此外，Tat-hspb 1可以诱导ccRCC细胞的溶酶体膜透化（LMP）和凋亡，而对正常上皮细胞的细胞毒性较小。tat-hspb 1可能是一种潜在的肾癌治疗药物。透明细胞肾细胞癌（ccRCC）是最常见的肾癌，其发病率在全球范围内呈上升趋势，死亡率高。生物活性肽被认为是一类重要的天然药物。我们应用基于质谱的肽组分析来探索人肾透明细胞癌和癌旁正常组织的肽谱。共鉴定了18，031个肽，其中105个独特的肽差异表达（在ccRCC组织中44个上调，61个下调）。通过生物信息学分析，我们最终选择了一个来自HSPB 1蛋白的肽（HSPB 1 N端区域的氨基酸12-35）。接下来，我们将这种肽与HIV-Tat融合，产生了一种名为Tat-hspb 1的新肽，并发现Tat-hspb 1抑制ccRCC细胞的活力，同时对正常上皮细胞的细胞毒性较小。此外，Tat-hspb 1还能诱导ccRCC细胞凋亡，抑制其增殖和迁移。此外，我们证明了Tat-hspb 1在进入ccRCC细胞后主要定位于溶酶体中，并诱导溶酶体膜透化（LMP）和从溶酶体释放组织蛋白酶D。总之，Tat-hspb 1有可能成为一种新的抗癌候选药物。
In this study, we discovered a novel endogenous peptide derived from HSPB1 protein through peptidomic analysis of human renal clear cell carcinoma and adjacent normal tissues. We generated a new peptide by conjugating this HSPB1-derived peptide with the HIV-Tat, named Tat-hspb1. We found that Tat-hspb1 could inhibit the proliferation and migration of ccRCC cells. Furthermore, Tat-hspb1 could induce lysosomal membrane permeabilization (LMP) and apoptosis of ccRCC cells while being less cytotoxic to normal epithelial cells. Tat-hspb1 may be a potential therapeutic agent for renal cancer. Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the peptide profile of human renal clear cell carcinoma and adjacent normal tissues. A total of 18,031 peptides were identified, of which 105 unique peptides were differentially expressed (44 were up-regulated and 61 were down-regulated in ccRCC tissues). Through bioinformatic analysis, we finally selected one peptide derived from the HSPB1 protein (amino acids 12–35 of the N-terminal region of HSPB1). Next, we fused this peptide to the HIV-Tat, generated a novel peptide named Tat-hspb1, and found that Tat-hspb1 inhibited ccRCC cells’ viability while being less cytotoxic to normal epithelial cells. Furthermore, Tat-hspb1 induced apoptosis and inhibited the proliferation and migration of ccRCC cells. Furthermore, we demonstrated that Tat-hspb1 was predominantly localized in lysosomes after entering the ccRCC cell and induced lysosomal membrane permeabilization (LMP) and the release of cathepsin D from lysosomes. Taken together, Tat-hspb1 has the potential to serve as a new anticancer drug candidate.
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DOI：
10.1038/nrm3999
发表时间：
2015-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Fuchs Y;Steller H
通讯作者：
Steller H
影响因子：
168.9
作者：
Escudier, Bernard;Pluzanska, Anna;Moore, Nicola
通讯作者：
Moore, Nicola
影响因子：
14.8
作者：
Degterev, Alexei;Hitomi, Junichi;Yuan, Junying
通讯作者：
Yuan, Junying
影响因子：
3.7
作者：
Jantas, Danuta;Chwastek, Jakub;Lason, Wladyslaw
通讯作者：
Lason, Wladyslaw
影响因子：
3.4
作者：
Dabestani, Saeed;Thorstenson, Andreas;Lundstam, Sven
通讯作者：
Lundstam, Sven