TY - JOUR
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
N1 - Funding Information:
This work was supported by the Canary Foundation, the LUN Gevity Foundation, the National Cancer Institute Early Detection Research Network, the Department of Defense (W81XWH-09-LCRP-CTRA and W81XWH-15-1-0127), the National Institutes of Health (U01 CA186150), Lung Cancer Specialized Program of Research Excellence (P50CA70907), the Cancer Center Support Grant from the National Institutes of Health (P30 CA016672), The University of Texas MD Anderson Cancer Center Moon Shots Program, and start-up funds from MD Anderson Cancer Center.
Publisher Copyright:
© The Author 2017.
PY - 2017/3
Y1 - 2017/3
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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U2 - 10.1093/jnci/djw231
DO - 10.1093/jnci/djw231
M3 - Article
C2 - 28376202
AN - SCOPUS:85018160687
SN - 0027-8874
VL - 109
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 3
ER -