Abstract
Cancer cells always require more nutrients, energy, and biosynthetic activity to sustain their rapid proliferation than normal cells. Previous studies have shown the impact of THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), on transcription regulation and cell-cycle arrest in numerous cancers, but its effects on cellular metabolism in cancer cells remain unknown. In this study we elucidated the anticancer mechanism of THZ1 in human non-small-cell lung cancer (NSCLC) cells. We showed that treatment with THZ1 (10−1000 nM) dose-dependently suppressed the proliferation of human NSCLC cell lines H1299, A549, H292, and H23, and markedly inhibited the migration of these NSCLC cells. Furthermore, treatment with THZ1 (50 nM) arrested cell cycle at G2/M phase and induced apoptosis in these NSCLC cell lines. More importantly, we revealed that treatment with THZ1 (50 nM) blocked the glycolysis pathway but had no effect on glutamine metabolism. We further demonstrated that THZ1 treatment altered the expression pattern of glutaminase 1 (GLS1) isoforms through promoting the ubiquitination and degradation of NUDT21. Combined treatment of THZ1 with a glutaminase inhibitor CB-839 (500 nM) exerted a more potent anti-proliferative effect in these NSCLC cell lines than treatment with THZ1 or CB-839 alone. Our results demonstrate that the inhibitory effect of THZ1 on the growth of human NSCLC cells is partially attributed to interfering with cancer metabolism. Thus, we provide a new potential therapeutic strategy for NSCLC treatment by combining THZ1 with the inhibitors of glutamine metabolism.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.
Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 2014;511:616–20.
Yee A, Nichols MA, Wu L, Hall FL, Kobayashi R, Xiong Y. Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. Cancer Res. 1995;55:6058–62.
Ni Z, Schwartz BE, Werner J, Suarez JR, Lis JT. Coordination of transcription, RNA processing, and surveillance by P-TEFb kinase on heat shock genes. Mol Cell. 2004;13:55–65.
Ho CK, Shuman S. Distinct roles for CTD Ser-2 and Ser-5 phosphorylation in the recruitment and allosteric activation of mammalian mRNA capping enzyme. Mol Cell. 1999;3:405–11.
Chapman RD, Heidemann M, Albert TK, Mailhammer R, Flatley A, Meisterernst M, et al. Transcribing RNA polymerase II is phosphorylated at CTD residue serine-7. Science. 2007;318:1780–2.
Fisher RP. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci. 2005;118:5171–80.
Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14:130–46.
Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014;159:1126–39.
Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014;26:909–22.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11–20.
Warburg O. Iron, the Oxygen-Carrier of Respiration-Ferment. Science. 1925;61:575–82.
Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.
Sandulache VC, Ow TJ, Pickering CR, Frederick MJ, Zhou G, Fokt I, et al. Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells. Cancer. 2011;117:2926–38.
Fischer CP, Bode BP, Souba WW. Adaptive alterations in cellular metabolism with malignant transformation. Ann Surg. 1998;227:627–34; discussion 34-6.
Kaplan O. Correspondence re: M. Fanciulli et al. Energy metabolism of human LoVo colon carcinoma cells: correlation to drug resistance and influence fo lonidamine. Clin. Cancer Res. 2000;6:1590–7, 4166–7.
Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008;283:28106–14.
Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.
Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. 2007;178:93–105.
Portais JC, Voisin P, Merle M, Canioni P. Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR. Biochimie. 1996;78:155–64.
Forbes NS, Meadows AL, Clark DS, Blanch HW. Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng. 2006;8:639–52.
Brand K. Glutamine and glucose metabolism during thymocyte proliferation. Pathw glutamine glutamate Metab Biochem J. 1985;228:353–61.
Eagle H, Oyama VI, Levy M, Horton CL, Fleischman R. The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J Biol Chem. 1956;218:607–16.
Elgadi KM, Meguid RA, Qian M, Souba WW, Abcouwer SF. Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiol Genom. 1999;1:51–62.
Szeliga M, Matyja E, Obara M, Grajkowska W, Czernicki T, Albrecht J. Relative expression of mRNAS coding for glutaminase isoforms in CNS tissues and CNS tumors. Neurochem Res. 2008;33:808–13.
van den Heuvel AP, Jing J, Wooster RF, Bachman KE. Analysis of glutamine dependency in non-small cell lung cancer: GLS1 splice variant GAC is essential for cancer cell growth. Cancer Biol Ther. 2012;13:1185–94.
Cunningham CC, Stossel TP, Kwiatkowski DJ. Enhanced motility in NIH 3T3 fibroblasts that overexpress gelsolin. Science. 1991;251:1233–6.
Larochelle S, Merrick KA, Terret ME, Wohlbold L, Barboza NM, Zhang C, et al. Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol Cell. 2007;25:839–50.
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892–9.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.
Szeliga M, Albrecht J. Opposing roles of glutaminase isoforms in determining glioblastoma cell phenotype. Neurochem Int. 2015;88:6–9.
Wilson KF, Erickson JW, Antonyak MA, Cerione RA. Rho GTPases and their roles in cancer metabolism. Trends Mol Med. 2013;19:74–82.
Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, et al. Allele-specific reprogramming of cancer metabolism by the long non-coding RNA CCAT2. Mol Cell. 2016;61:520–34.
Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18:207–19.
Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13:890–901.
Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer--Recent advances and future perspectives. Int J Cancer. 2016;138:2549–61.
Wang Y, Zhang T, Kwiatkowski N, Abraham BJ, Lee TI, Xie S, et al. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell. 2015;163:174–86.
Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9:425–34.
Jiang YY, Lin DC, Mayakonda A, Hazawa M, Ding LW, Chien WW. et al. Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. Gut. 2017;66:1358–68.
Harrod A, Fulton J, Nguyen VTM, Periyasamy M, Ramos-Garcia L, Lai CF, et al. Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer. Oncogene. 2017;36:2286–96.
Wang L, Xiong H, Wu F, Zhang Y, Wang J, Zhao L, et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 2014;8:1461–74.
Bondy CA, Cheng CM. Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol. 2004;490:25–31.
Deberardinis RJ, Lum JJ, Thompson CB. Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem. 2006;281:37372–80.
Momcilovic M, Bailey ST, Lee JT, Fishbein MC, Magyar C, Braas D, et al. Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR mutant lung cancer. Cell Rep. 2017;18:601–10.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (91639106 to H-bX, 81660041 to L-bD), the National Basic Research Program of China (2013CB531103 to H-bX and L-bD), and the Jiangxi Province Science Foundation for Youths (20122BAB215020 to H-wC).
Author contribution
H-bX and H-dS designed the experiments and interpreted data. Z-jC, D-lM and Q-yS performed the experiments. X-lT, X-lW, L-bD and Z-jC analyzed data. Z-jC and H-bX wrote the paper.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare that they have no financial, professional, or other conflicts related to this manuscript.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Cheng, ZJ., Miao, DL., Su, QY. et al. THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. Acta Pharmacol Sin 40, 814–822 (2019). https://doi.org/10.1038/s41401-018-0187-3
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41401-018-0187-3
Keywords
This article is cited by
-
The BET PROTAC inhibitor GNE-987 displays anti-tumor effects by targeting super-enhancers regulated gene in osteosarcoma
BMC Cancer (2024)
-
CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer
Journal of Hematology & Oncology (2020)
-
Glutaminases regulate glutathione and oxidative stress in cancer
Archives of Toxicology (2020)
-
The P2X7 purinergic receptor: a potential therapeutic target for lung cancer
Journal of Cancer Research and Clinical Oncology (2020)
