PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40)

Tejaswini Subbannayya, Pamela Leal-Rojas, Alex Zhavoronkov, Ivan V. Ozerov, Mikhail Korzinkin, Niraj Babu, Aneesha Radhakrishnan, Sandip Chavan, Remya Raja, Sneha M. Pinto, Arun H. Patil, Mustafa A. Barbhuiya, Prashant Kumar, Rafael Guerrero-Preston, Sanjay Navani, Pramod K. Tiwari, Rekha Vijay Kumar, T. S.Keshava Prasad, Juan Carlos Roa, Akhilesh PandeyDavid Sidransky, Harsha Gowda, Evgeny Izumchenko, Aditi Chatterjee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of Cell Communication and Signaling
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Gallbladder Neoplasms
Cell proliferation
Proline
Phosphotransferases
Cell Proliferation
Substrates
Cells
Phosphorylation
Microarrays
Labeling
Cell Line
Tissue
Disease Management
Gallbladder
Chemical analysis
Cell Survival
Adenocarcinoma
Therapeutics
Biomarkers
Proteins

Keywords

  • Cell survival
  • Gastrointestinal cancer
  • mTOR signaling
  • Phosphoproteomics
  • SGI-1776
  • Targeted therapy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40). / Subbannayya, Tejaswini; Leal-Rojas, 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; Guerrero-Preston, 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.

In: Journal of Cell Communication and Signaling, 01.01.2019.

Research output: Contribution to journalArticle

Subbannayya, T, Leal-Rojas, P, Zhavoronkov, A, Ozerov, IV, Korzinkin, M, Babu, N, Radhakrishnan, A, Chavan, S, Raja, R, Pinto, SM, Patil, AH, Barbhuiya, MA, Kumar, P, Guerrero-Preston, R, Navani, S, Tiwari, PK, Kumar, RV, Prasad, TSK, Roa, JC, Pandey, A, Sidransky, D, Gowda, H, Izumchenko, E & Chatterjee, A 2019, 'PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40)', Journal of Cell Communication and Signaling. https://doi.org/10.1007/s12079-018-00503-5
Subbannayya, Tejaswini ; Leal-Rojas, 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 ; Guerrero-Preston, 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. / PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40). In: Journal of Cell Communication and Signaling. 2019.
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AU - Subbannayya, Tejaswini

AU - Leal-Rojas, Pamela

AU - Zhavoronkov, Alex

AU - Ozerov, Ivan V.

AU - Korzinkin, Mikhail

AU - Babu, Niraj

AU - Radhakrishnan, Aneesha

AU - Chavan, Sandip

AU - Raja, Remya

AU - Pinto, Sneha M.

AU - Patil, Arun H.

AU - Barbhuiya, Mustafa A.

AU - Kumar, Prashant

AU - Guerrero-Preston, Rafael

AU - Navani, Sanjay

AU - Tiwari, Pramod K.

AU - Kumar, Rekha Vijay

AU - Prasad, T. S.Keshava

AU - Roa, Juan Carlos

AU - Pandey, Akhilesh

AU - Sidransky, David

AU - Gowda, Harsha

AU - Izumchenko, Evgeny

AU - Chatterjee, Aditi

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N2 - 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.

AB - 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.

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KW - Gastrointestinal cancer

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KW - Phosphoproteomics

KW - SGI-1776

KW - Targeted therapy

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