Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma

Muge Celiktas, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F. Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B. Dennison, Edwin J. Ostrin, Hong Wang, Carmen Behrens, Kim Anh Do, Adi F. Gazdar, Samir M. Hanash, Ayumu Taguchi

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Abstract

Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95% confidence interval = 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.

Original languageEnglish (US)
Article numberdjw231
JournalJournal of the National Cancer Institute
Volume109
Issue number3
DOIs
StatePublished - 2017

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Carbamyl Phosphate
Ligases
Phosphotransferases
Liver
Growth
gemcitabine
Cell Line
Adenocarcinoma of lung
Pemetrexed
Tissue Array Analysis
Survival
Metabolome
Proteome
Proteomics
Nucleic Acids

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Celiktas, M., Tanaka, I., Tripathi, S. C., Fahrmann, J. F., Aguilar-Bonavides, C., Villalobos, P., ... Taguchi, A. (2017). Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma. Journal of the National Cancer Institute, 109(3), [djw231]. https://doi.org/10.1093/jnci/djw231

Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma. / Celiktas, Muge; Tanaka, Ichidai; Tripathi, Satyendra Chandra; Fahrmann, Johannes F.; Aguilar-Bonavides, Clemente; Villalobos, Pamela; Delgado, Oliver; Dhillon, Dilsher; Dennison, Jennifer B.; Ostrin, Edwin J.; Wang, Hong; Behrens, Carmen; Do, Kim Anh; Gazdar, Adi F.; Hanash, Samir M.; Taguchi, Ayumu.

In: Journal of the National Cancer Institute, Vol. 109, No. 3, djw231, 2017.

Research output: Contribution to journalArticle

Celiktas, M, Tanaka, I, Tripathi, SC, Fahrmann, JF, Aguilar-Bonavides, C, Villalobos, P, Delgado, O, Dhillon, D, Dennison, JB, Ostrin, EJ, Wang, H, Behrens, C, Do, KA, Gazdar, AF, Hanash, SM & Taguchi, A 2017, 'Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma', Journal of the National Cancer Institute, vol. 109, no. 3, djw231. https://doi.org/10.1093/jnci/djw231
Celiktas M, Tanaka I, Tripathi SC, Fahrmann JF, Aguilar-Bonavides C, Villalobos P et al. Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma. Journal of the National Cancer Institute. 2017;109(3). djw231. https://doi.org/10.1093/jnci/djw231
Celiktas, Muge ; Tanaka, Ichidai ; Tripathi, Satyendra Chandra ; Fahrmann, Johannes F. ; Aguilar-Bonavides, Clemente ; Villalobos, Pamela ; Delgado, Oliver ; Dhillon, Dilsher ; Dennison, Jennifer B. ; Ostrin, Edwin J. ; Wang, Hong ; Behrens, Carmen ; Do, Kim Anh ; Gazdar, Adi F. ; Hanash, Samir M. ; Taguchi, Ayumu. / Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 3.
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title = "Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma",
abstract = "Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7{\%} of LKB1-negative LADC, and only 5.0{\%} of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95{\%} confidence interval = 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.",
author = "Muge Celiktas and Ichidai Tanaka and Tripathi, {Satyendra Chandra} and Fahrmann, {Johannes F.} and Clemente Aguilar-Bonavides and Pamela Villalobos and Oliver Delgado and Dilsher Dhillon and Dennison, {Jennifer B.} and Ostrin, {Edwin J.} and Hong Wang and Carmen Behrens and Do, {Kim Anh} and Gazdar, {Adi F.} and Hanash, {Samir M.} and Ayumu Taguchi",
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T1 - Role of CPS1 in cell growth, metabolism, and prognosis in LKB1-inactivated lung adenocarcinoma

AU - Celiktas, Muge

AU - Tanaka, Ichidai

AU - Tripathi, Satyendra Chandra

AU - Fahrmann, Johannes F.

AU - Aguilar-Bonavides, Clemente

AU - Villalobos, Pamela

AU - Delgado, Oliver

AU - Dhillon, Dilsher

AU - Dennison, Jennifer B.

AU - Ostrin, Edwin J.

AU - Wang, Hong

AU - Behrens, Carmen

AU - Do, Kim Anh

AU - Gazdar, Adi F.

AU - Hanash, Samir M.

AU - Taguchi, Ayumu

PY - 2017

Y1 - 2017

N2 - Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95% confidence interval = 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.

AB - Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio = 3.03, 95% confidence interval = 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.

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