1. PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40)
- Author
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Aditi Chatterjee, Pamela Leal-Rojas, Mikhail Korzinkin, Evgeny Izumchenko, Akhilesh Pandey, Tejaswini Subbannayya, Niraj Babu, Aneesha Radhakrishnan, David Sidransky, T. S. Keshava Prasad, Sneha M. Pinto, Mustafa A. Barbhuiya, Rafael Guerrero-Preston, Sandip Chavan, Rekha V. Kumar, Juan Carlos Roa, Sanjay Navani, Harsha Gowda, Pramod Kumar Tiwari, Prashant Kumar, Alex Zhavoronkov, Ivan V. Ozerov, Remya Raja, and Arun H. Patil
- Subjects
0301 basic medicine ,Tissue microarray ,Kinase ,Cell growth ,PIM1 ,Cell Biology ,Biology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cell culture ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Gastrointestinal cancer ,Gallbladder cancer ,Molecular Biology ,Protein kinase B ,Research Article - Abstract
Gallbladder cancer (GBC) is a rare malignancy, associated with poor disease prognosis with a 5-year survival of only 20%. This has been attributed to late presentation of the disease, lack of early diagnostic markers and limited efficacy of therapeutic interventions. Elucidation of molecular events in GBC can contribute to better management of the disease by aiding in the identification of therapeutic targets. To identify aberrantly activated signaling events in GBC, tandem mass tag-based quantitative phosphoproteomic analysis of five GBC cell lines was carried out. Proline-rich Akt substrate 40 kDa (PRAS40) was one of the proteins found to be hyperphosphorylated in all the invasive GBC cell lines. Tissue microarray-based immunohistochemical labeling of phospho-PRAS40 (T246) revealed moderate to strong staining in 77% of the primary gallbladder adenocarcinoma cases. Regulation of PRAS40 activity by inhibiting its upstream kinase PIM1 resulted in a significant decrease in cell proliferation, colony forming and invasive ability of GBC cells. Our results support the role of PRAS40 phosphorylation in GBC cell survival and aggressiveness. This study also elucidates phospho-PRAS40 as a clinical marker in GBC and the role of PIM1 as a therapeutic target in GBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12079-018-00503-5) contains supplementary material, which is available to authorized users.
- Published
- 2019