4.7 Article

Molecular Profiling Associated with Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2)-Mediated Carcinogenesis in Gastric Cancer

期刊

JOURNAL OF PROTEOME RESEARCH
卷 20, 期 5, 页码 2687-2703

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.1c00008

关键词

CAMKK2; gastric cancer; STO-609; mass spectrometry

资金

  1. Karnataka Biotechnology and Information Technology Services (KBITS), the Government of Karnataka under the Biotechnology Skill Enhancement Programme in Multiomics Technology [BiSEP GO ITD 02 MDA 2017]
  2. Indian Council of Medical Research (ICMR), Government of India
  3. University Grants Commission (UGC), Government of India

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CAMKK2 is highly expressed in gastric cancer and promotes tumor progression. Inhibiting CAMKK2 can reduce the migration, invasion, and proliferation abilities of gastric cancer cells. Quantitative proteomic analysis identified several key proteins involved in cell division and proliferation that were downregulated upon CAMKK2 inhibition, suggesting CAMKK2 as a potential therapeutic target in gastric cancer.
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide. We showed previously that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a serine-threonine kinase, is highly expressed in gastric cancer and leads to progression. In the present study, we identified the molecular networks involved in CAMKK2-mediated progression of gastric adenocarcinoma. Treatment of gastric cancer cell lines with a CAMKK2 inhibitor, STO-609, resulted in decreased cell migration, invasion, and colony-forming ability and a G1/S-phase arrest. In addition, tandem mass tag (TMT)-based quantitative proteomic analysis resulted in the identification of 7609 proteins, of which 219 proteins were found to be overexpressed and 718 downregulated (1.5-fold). Our data identified several key downregulated proteins involved in cell division and cell proliferation, which included DNA replication licensing factors, replication factor C, origin recognition complex, replication protein A and GINS, and mesenchymal markers, upon CAMKK2 inhibition. Immunoblotting and immunofluorescence results showed concordance with our mass spectroscopy data. Taken together, our study supports CAMKK2 as a novel therapeutic target in gastric cancer.

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