Phosphoproteomic analysis of metformin signaling in colorectal cancer cells elucidates mechanism of action and potential therapeutic opportunities.
Phosphoproteomic analysis of metformin signaling in colorectal cancer cells elucidates mechanism of action and potential therapeutic opportunities.
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DOI：
10.1002/ctm2.1179
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发表时间：
2023-02
影响因子：
10.6
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中科院分区：
文献类型：
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双胍类药物二甲双胍是一种安全且广泛用于治疗2型糖尿病的处方药。有趣的是，数以百计的临床试验已经开始评估二甲双胍在预防和治疗包括结直肠癌（CRC）在内的癌症中的潜在作用。然而，“二甲双胍信号”仍然存在争议。为了探究二甲双胍在结直肠癌中诱导的细胞信号传导，并探索二甲双胍重新连接的磷酸化网络的可药物性，我们对12个分子异质性结直肠癌细胞系进行了磷蛋白质组学、生物信息学和细胞增殖试验的综合分析。使用高分辨率数据独立分析质谱（DIA - MS），我们在短期和长期二甲双胍治疗的CRC细胞中监测了总共10,142个蛋白质和56,080个磷酸位点（P位点）。我们发现二甲双胍在长期内倾向于主要重塑细胞信号，并且仅最低限度地调节总蛋白质组表达水平。引人注目的是，基于推断激酶/磷酸酶活性和细胞信号重建的网络分析，在CRC小组中，二甲双胍的磷酸化信号反应是高度异质性的。“MetScore”测定了每个P位点的二甲双胍相关性，揭示了二甲双胍信号传导中新的和强大的磷酸化节点和途径。最后，我们利用二甲双胍P位点特征来确定药效学相互作用，并确认了一些候选的二甲双胍相互作用药物，包括navitoclax（一种BCL‐2/BCL‐xL抑制剂）。总之，我们提供了一个全面的磷蛋白质组学资源来探索二甲双胍诱导的潜在癌症治疗的细胞信号。此资源可通过https://yslproteomics.shinyapps.io/Metformin/访问。结直肠癌（CRC）中二甲双胍信号传导的深入蛋白质组学和磷酸化蛋白质组学研究。对二甲双胍的磷酸化蛋白组学反应在结直肠癌细胞系中是高度异质性的。建立磷酸化位点特异性MetScore，确定了55个最重要的二甲双胍特征位点。利用磷蛋白组学发现CRC中潜在的二甲双胍-药物相互作用，例如navitoclax。
The biguanide drug metformin is a safe and widely prescribed drug for type 2 diabetes. Interestingly, hundreds of clinical trials have been set to evaluate the potential role of metformin in the prevention and treatment of cancer including colorectal cancer (CRC). However, the “metformin signaling” remains controversial. To interrogate cell signaling induced by metformin in CRC and explore the druggability of the metformin‐rewired phosphorylation network, we performed integrative analysis of phosphoproteomics, bioinformatics, and cell proliferation assays on a panel of 12 molecularly heterogeneous CRC cell lines. Using the high‐resolute data‐independent analysis mass spectrometry (DIA‐MS), we monitored a total of 10,142 proteins and 56,080 phosphosites (P‐sites) in CRC cells upon a short‐ and a long‐term metformin treatment. We found that metformin tended to primarily remodel cell signaling in the long‐term and only minimally regulated the total proteome expression levels. Strikingly, the phosphorylation signaling response to metformin was highly heterogeneous in the CRC panel, based on a network analysis inferring kinase/phosphatase activities and cell signaling reconstruction. A “MetScore” was determined to assign the metformin relevance of each P‐site, revealing new and robust phosphorylation nodes and pathways in metformin signaling. Finally, we leveraged the metformin P‐site signature to identify pharmacodynamic interactions and confirmed a number of candidate metformin‐interacting drugs, including navitoclax, a BCL‐2/BCL‐xL inhibitor. Together, we provide a comprehensive phosphoproteomic resource to explore the metformin‐induced cell signaling for potential cancer therapeutics. This resource can be accessed at https://yslproteomics.shinyapps.io/Metformin/. An in‐depth proteomic and phosphoproteomic resource on metformin signaling in colorectal cancer (CRC). The phosphoproteomic response to metformin was highly heterogeneous in CRC cell lines. Establishing a phosphorylation site‐specific MetScore, which identified 55 most significant metformin signature sites. Leveraging the phosphoproteomics to discover potential metformin∼drug interactions in CRC, e.g., navitoclax.
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DOI：
10.3390/ph14020122
发表时间：
2021-02-05
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Drzewoski J;Hanefeld M
通讯作者：
Hanefeld M
影响因子：
--
作者：
Du L;Wang M;Kang Y;Li B;Guo M;Cheng Z;Bi C
通讯作者：
Bi C
影响因子：
64.8
作者：
Galmozzi, Andrea;Kok, Bernard P.;Saez, Enrique
通讯作者：
Saez, Enrique
影响因子：
7
作者：
Bruderer, Roland;Muntel, Jan;Reiter, Lukas
通讯作者：
Reiter, Lukas
DOI：
10.1074/mcp.ra117.000314
发表时间：
2017-12
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Bruderer R;Bernhardt OM;Gandhi T;Xuan Y;Sondermann J;Schmidt M;Gomez-Varela D;Reiter L
通讯作者：
Reiter L