Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin.
Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin.
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DOI：
10.18632/oncotarget.3579
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发表时间：
2015-05-10
期刊：
影响因子：
--
通讯作者：
Mathivanan S
中科院分区：
文献类型：
--
作者：
Gangoda L;Keerthikumar S;Fonseka P;Edgington LE;Ang CS;Ozcitti C;Bogyo M;Parker BS;Mathivanan S
神经母细胞瘤起源于交感神经系统，占儿童癌症死亡率的15%。据报道，超过20%的患者发生癌基因N-Myc扩增。虽然N-Myc扩增状态与较高的肿瘤侵袭性和治疗抵抗力密切相关，但N-Myc在疾病侵袭性进展中的作用尚不清楚。N-Myc作为一种转录因子，可以调节在肿瘤发生中起关键作用的关键蛋白的分泌。表征可溶性分泌蛋白或分泌组将有助于理解它们在肿瘤微环境中的作用，例如促进癌细胞侵袭和对治疗的抗性。本研究的目的是鉴定人恶性神经母细胞瘤SK-N-BE 2（N-Myc扩增，更具侵袭性）和SH-SY 5 Y（N-Myc非扩增，侵袭性较低）细胞的分泌组。对来自SK-N-BE 2和SH-SY 5 Y细胞系的条件培养基进行蛋白质组学分析。我们报告了一个目录的894个蛋白质中分离的分泌组从两个神经母细胞瘤细胞系，SK-N-BE 2和SH-SY 5 Y。使用FunRich软件的功能富集分析鉴定了与侵袭性N-Myc扩增的SK-N-BE 2分泌组中的半胱氨酸肽酶活性有关的蛋白质的分泌增强，与致瘤性较低的SH-SY 5 Y细胞相比。基于蛋白质-蛋白质相互作用的网络分析强调了组织蛋白酶和上皮-间充质转化子网络的富集。第一次，抑制剂对组织蛋白酶的抑制使耐药SK-N-BE 2细胞对阿霉素敏感，并降低了其迁移潜力。N-Myc扩增（更具侵袭性）和非扩增（侵袭性较低）的神经母细胞瘤细胞的分泌组蛋白的数据集代表了神经母细胞瘤分泌组的第一个库存。该研究还强调了组织蛋白酶在N-Myc扩增的神经母细胞瘤发病机制中的重要作用。由于N-Myc扩增与侵袭性神经母细胞瘤和基于化疗的治疗失败相关，因此与组织蛋白酶抑制剂联合治疗可能是疾病管理的更好途径。
Neuroblastoma arises from the sympathetic nervous system and accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc is reported to occur in more than 20% of patients. While N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressive progression of the disease is poorly understood. N-Myc being a transcription factor can modulate the secretion of key proteins that may play a pivotal role in tumorigenesis. Characterising the soluble secreted proteins or secretome will aid in understanding their role in the tumour microenvironment, such as promoting cancer cell invasion and resistance to treatment. The aim of this study is to characterise the secretome of human malignant neuroblastoma SK-N-BE2 (N-Myc amplified, more aggressive) and SH-SY5Y (N-Myc non-amplified, less aggressive) cells. Conditioned media from SK-N-BE2 and SH-SY5Y cell lines were subjected to proteomics analysis. We report a catalogue of 894 proteins identified in the secretome isolated from the two neuroblastoma cell lines, SK-N-BE2 and SH-SY5Y. Functional enrichment analysis using FunRich software identified enhanced secretion of proteins implicated in cysteine peptidase activity in the aggressive N-Myc amplified SK-N-BE2 secretome compared to the less tumorigenic SH-SY5Y cells. Protein-protein interaction-based network analysis highlighted the enrichment of cathepsin and epithelial-to-mesenchymal transition sub-networks. For the first time, inhibition of cathepsins by inhibitors sensitized the resistant SK-N-BE2 cells to doxorubicin as well as decreased its migratory potential. The dataset of secretome proteins of N-Myc amplified (more aggressive) and non-amplified (less aggressive) neuroblastoma cells represent the first inventory of neuroblastoma secretome. The study also highlights the prominent role of cathepsins in the N-Myc amplified neuroblastoma pathogenesis. As N-Myc amplification correlates with aggressive neuroblastoma and chemotherapy-based treatment failure, co-treatment with cathepsin inhibitors might be a better avenue for disease management.
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影响因子：
3.4
作者：
Kalra, Hina;Adda, Christopher G.;Mathivanan, Suresh
通讯作者：
Mathivanan, Suresh
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
3.8
作者：
Anastassiou D;Rumjantseva V;Cheng W;Huang J;Canoll PD;Yamashiro DJ;Kandel JJ
通讯作者：
Kandel JJ
影响因子：
3.3
作者：
Mathivanan, Suresh;Ji, Hong;Simpson, Richard J.
通讯作者：
Simpson, Richard J.
影响因子：
4
作者：
Goodman, LA;Liu, BCS;Wada, RK
通讯作者：
Wada, RK