Open AccessPIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline‐rich Akt substrate of 40 kDa (PRAS40)
Author(s) -
Subbannayya Tejaswini,
LealRojas Pamela,
Zhavoronkov Alex,
Ozerov Ivan V.,
Korzinkin Mikhail,
Babu Niraj,
Radhakrishnan Aneesha,
Chavan Sandip,
Raja Remya,
Pinto Sneha M.,
Patil Arun H.,
Barbhuiya Mustafa A.,
Kumar Prashant,
GuerreroPreston Rafael,
Navani Sanjay,
Tiwari Pramod K.,
Kumar Rekha Vijay,
Prasad T. S. Keshava,
Roa Juan Carlos,
Pandey Akhilesh,
Sidransky David,
Gowda Harsha,
Izumchenko Evgeny,
Chatterjee Aditi
Publication year - 2019
Publication title -
journal of cell communication and signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-018-00503-5
Subject(s) - protein kinase b , cancer research , gallbladder cancer , pi3k/akt/mtor pathway , gallbladder , cancer , cell growth , biology , medicine , pathology , signal transduction , microbiology and biotechnology , biochemistry
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.