TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways

Karnika Singh; Chunhua Han; Jessica L Fleming; Aline P Becker; Joseph McElroy; Tiantian Cui; Benjamin Johnson; Ashok Kumar; Ebin Sebastian; Christian A Showalter; Morgan S Schrock; Matthew K Summers; Valesio Becker; Zhen-Yue Tong; Xiaomei Meng; Heather R Manring; Monica Venere; Erica H Bell; Pierre A Robe; A L Grosu; S Jaharul Haque; Arnab Chakravarti

doi:10.1038/s41598-023-32983-w

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways

Karnika Singh, Chunhua Han, Jessica L Fleming, Aline P Becker, Joseph McElroy, Tiantian Cui, Benjamin Johnson, Ashok Kumar, Ebin Sebastian, Christian A Showalter, Morgan S Schrock, Matthew K Summers, Valesio Becker, Zhen-Yue Tong, Xiaomei Meng, Heather R Manring, Monica Venere, Erica H Bell, Pierre A Robe, A L GrosuS Jaharul Haque, Arnab Chakravarti^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

Original language	English
Article number	12424
Journal	Scientific Reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-32983-w
Publication status	Published - 1 Aug 2023

Keywords

Animals
Apoptosis/genetics
Brain Neoplasms/drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm/genetics
Glioblastoma/drug therapy
Mice
Mitogen-Activated Protein Kinase Kinases
Proto-Oncogene Proteins c-akt/metabolism
Temozolomide/pharmacology

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Singh, K., Han, C., Fleming, J. L., Becker, A. P., McElroy, J., Cui, T., Johnson, B., Kumar, A., Sebastian, E., Showalter, C. A., Schrock, M. S., Summers, M. K., Becker, V., Tong, Z.-Y., Meng, X., Manring, H. R., Venere, M., Bell, E. H., Robe, P. A., ... Chakravarti, A. (2023). TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways. Scientific Reports, 13(1), Article 12424. https://doi.org/10.1038/s41598-023-32983-w

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title = "TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways",

abstract = "GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.",

keywords = "Animals, Apoptosis/genetics, Brain Neoplasms/drug therapy, Cell Line, Tumor, Drug Resistance, Neoplasm/genetics, Glioblastoma/drug therapy, Mice, Mitogen-Activated Protein Kinase Kinases, Proto-Oncogene Proteins c-akt/metabolism, Temozolomide/pharmacology",

author = "Karnika Singh and Chunhua Han and Fleming, {Jessica L} and Becker, {Aline P} and Joseph McElroy and Tiantian Cui and Benjamin Johnson and Ashok Kumar and Ebin Sebastian and Showalter, {Christian A} and Schrock, {Morgan S} and Summers, {Matthew K} and Valesio Becker and Zhen-Yue Tong and Xiaomei Meng and Manring, {Heather R} and Monica Venere and Bell, {Erica H} and Robe, {Pierre A} and Grosu, {A L} and Haque, {S Jaharul} and Arnab Chakravarti",

note = "Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2023",

month = aug,

day = "1",

doi = "10.1038/s41598-023-32983-w",

language = "English",

volume = "13",

journal = "Scientific Reports",

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Singh, K, Han, C, Fleming, JL, Becker, AP, McElroy, J, Cui, T, Johnson, B, Kumar, A, Sebastian, E, Showalter, CA, Schrock, MS, Summers, MK, Becker, V, Tong, Z-Y, Meng, X, Manring, HR, Venere, M, Bell, EH, Robe, PA, Grosu, AL, Haque, SJ & Chakravarti, A 2023, 'TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways', Scientific Reports, vol. 13, no. 1, 12424. https://doi.org/10.1038/s41598-023-32983-w

TY - JOUR

T1 - TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways

AU - Singh, Karnika

AU - Han, Chunhua

AU - Fleming, Jessica L

AU - Becker, Aline P

AU - McElroy, Joseph

AU - Cui, Tiantian

AU - Johnson, Benjamin

AU - Kumar, Ashok

AU - Sebastian, Ebin

AU - Showalter, Christian A

AU - Schrock, Morgan S

AU - Summers, Matthew K

AU - Becker, Valesio

AU - Tong, Zhen-Yue

AU - Meng, Xiaomei

AU - Manring, Heather R

AU - Venere, Monica

AU - Bell, Erica H

AU - Robe, Pierre A

AU - Grosu, A L

AU - Haque, S Jaharul

AU - Chakravarti, Arnab

PY - 2023/8/1

Y1 - 2023/8/1

N2 - GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

AB - GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

KW - Animals

KW - Apoptosis/genetics

KW - Brain Neoplasms/drug therapy

KW - Cell Line, Tumor

KW - Drug Resistance, Neoplasm/genetics

KW - Glioblastoma/drug therapy

KW - Mice

KW - Mitogen-Activated Protein Kinase Kinases

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Temozolomide/pharmacology

UR - http://www.scopus.com/inward/record.url?scp=85166150575&partnerID=8YFLogxK

U2 - 10.1038/s41598-023-32983-w

DO - 10.1038/s41598-023-32983-w

M3 - Article

C2 - 37528172

SN - 2045-2322

VL - 13

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 12424

ER -

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways

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