Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

The Expression of Glutaminases and their Association with Clinicopathological Parameters in the Head and Neck Cancers

Author(s): Haneen A. Basheer*, Lina Elsalem, Anwar Salem, Artysha Tailor, Keith Hunter and Kamyar Afarinkia

Volume 22, Issue 2, 2022

Published on: 03 March, 2022

Page: [169 - 179] Pages: 11

DOI: 10.2174/1568009622666211224111425

Price: $65

Abstract

Background: The increased glutamine metabolism is a characteristic feature of cancer cells. The interconversion between glutamine and glutamate is catalyzed by two glutaminase isoforms, GLS1 and GLS2, which appear to have different roles in different types of cancer. We investigated for the first time the protein expression of GLS1 and GLS2, and their correlation with advanced clinicopathological parameters in head and neck cancers.

Methods: Consecutive slides from a tissue microarray comprised of 80 samples ranging from normal to metastatic were stained immunohistochemically for GLS1, GLS2, HIF-1α or CD147. Following analysis by two expert pathologists, we carried out a statistical analysis of the scores.

Results: GLS1 and GLS2 were found to be upregulated at the protein level in head and neck tumours compared to normal tissues, and this increased expression correlated positively (GLS1) and negatively (GLS2) with tumor grade, indicating a shift of expression between GLS enzyme isoforms based on tumor differentiation. Increased expression of GLS1 was associated with high CD147 expression, and elevated GLS2 expression was associated with both high CD147 and high HIF-1α expressions. The correlation of the GLS1 and GLS2 with HIF-1α or CD147 was strongly associated with more advanced clinicopathological parameters.

Conclusion: The increased expression of GLS1 and GLS2 may be explored as a new treatment for head and neck cancers.

Keywords: Glutaminases, GLS1, GLS2, CD147, immunohistochemistry, head and neck cancers.

« Previous
Graphical Abstract

[1]
Thompson-Harvey, A.; Yetukuri, M.; Hansen, A.R.; Simpson, M.C.; Adjei Boakye, E.; Varvares, M.A.; Osazuwa-Peters, N. Rising incidence of late-stage head and neck cancer in the United States. Cancer, 2020, 126(5), 1090-1101.
[http://dx.doi.org/10.1002/cncr.32583] [PMID: 31722124]
[2]
Guidi, A.; Codecà, C.; Ferrari, D. Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: A systematic review. Med. Oncol., 2018, 35(3), 37.
[http://dx.doi.org/10.1007/s12032-018-1096-5] [PMID: 29441454]
[3]
Brands, M.T.; Smeekens, E.A.J.; Takes, R.P.; Kaanders, J.H.A.M.; Verbeek, A.L.M.; Merkx, M.A.W.; Geurts, S.M.E. Time patterns of recurrence and second primary tumors in a large cohort of patients treated for oral cavity cancer. Cancer Med., 2019, 8(12), 5810-5819.
[http://dx.doi.org/10.1002/cam4.2124] [PMID: 31400079]
[4]
Teicher, B.A.; Linehan, W.M.; Helman, L.J. Targeting cancer metabolism. Clin. Cancer Res., 2012, 18(20), 5537-5545.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2587] [PMID: 23071355]
[5]
Liberti, M.V.; Locasale, J.W. The Warburg effect: How does it benefit cancer cells? Trends Biochem. Sci., 2016, 41(3), 211-218.
[http://dx.doi.org/10.1016/j.tibs.2015.12.001] [PMID: 26778478]
[6]
Curthoys, N.P.; Watford, M. Regulation of glutaminase activity and glutamine metabolism. Annu. Rev. Nutr., 1995, 15, 133-159.
[http://dx.doi.org/10.1146/annurev.nu.15.070195.001025] [PMID: 8527215]
[7]
Aledo, J.C.; Gómez-Fabre, P.M.; Olalla, L.; Márquez, J. Identification of two human glutaminase loci and tissue-specific expression of the two related genes. Mamm. Genome, 2000, 11(12), 1107-1110.
[http://dx.doi.org/10.1007/s003350010190] [PMID: 11130979]
[8]
Xiang, L.; Mou, J.; Shao, B.; Wei, Y.; Liang, H.; Takano, N.; Semenza, G.L.; Xie, G. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis., 2019, 10(2), 40.
[http://dx.doi.org/10.1038/s41419-018-1291-5] [PMID: 30674873]
[9]
Son, J.; Lyssiotis, C.A.; Ying, H.; Wang, X.; Hua, S.; Ligorio, M.; Perera, R.M.; Ferrone, C.R.; Mullarky, E.; Shyh-Chang, N.; Kang, Y.; Fleming, J.B.; Bardeesy, N.; Asara, J.M.; Haigis, M.C.; DePinho, R.A.; Cantley, L.C.; Kimmelman, A.C. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 2013, 496(7443), 101-105.
[http://dx.doi.org/10.1038/nature12040] [PMID: 23535601]
[10]
Ren, L.; Ruiz-Rodado, V.; Dowdy, T.; Huang, S.; Issaq, S.H.; Beck, J.; Wang, H.; Tran Hoang, C.; Lita, A.; Larion, M.; LeBlanc, A.K. Glutaminase-1 (GLS1) inhibition limits metastatic progression in osteosarcoma. Cancer Metab., 2020, 8(1), 4.
[http://dx.doi.org/10.1186/s40170-020-0209-8] [PMID: 32158544]
[11]
Gross, M.I.; Demo, S.D.; Dennison, J.B.; Chen, L.; Chernov-Rogan, T.; Goyal, B.; Janes, J.R.; Laidig, G.J.; Lewis, E.R.; Li, J.; Mackinnon, A.L.; Parlati, F.; Rodriguez, M.L.; Shwonek, P.J.; Sjogren, E.B.; Stanton, T.F.; Wang, T.; Yang, J.; Zhao, F.; Bennett, M.K. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther., 2014, 13(4), 890-901.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0870] [PMID: 24523301]
[12]
Shen, Y.A.; Hong, J.; Asaka, R.; Asaka, S.; Hsu, F.C.; Suryo Rahmanto, Y.; Jung, J.G.; Chen, Y.W.; Yen, T.T.; Tomaszewski, A.; Zhang, C.; Attarwala, N.; DeMarzo, A.M.; Davidson, B.; Chuang, C.M.; Chen, X.; Gaillard, S.; Le, A.; Shih, I.M.; Wang, T.L. Inhibition of the MYC-regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant ovarian cancers. Cancer Res., 2020, 80(20), 4514-4526.
[PMID: 32859605]
[13]
Lee, Y.Z.; Yang, C.W.; Chang, H.Y.; Hsu, H.Y.; Chen, I.S.; Chang, H.S.; Lee, C.H.; Lee, J.C.; Kumar, C.R.; Qiu, Y.Q.; Chao, Y.S.; Lee, S.J. Discovery of selective inhibitors of Glutaminase-2, which inhibit mTORC1, activate autophagy and inhibit proliferation in cancer cells. Oncotarget, 2014, 5(15), 6087-6101.
[http://dx.doi.org/10.18632/oncotarget.2173] [PMID: 25026281]
[14]
Koch, K.; Hartmann, R.; Tsiampali, J.; Uhlmann, C.; Nickel, A-C.; He, X.; Kamp, M.A.; Sabel, M.; Barker, R.A.; Steiger, H-J.; Hänggi, D.; Willbold, D.; Maciaczyk, J.; Kahlert, U.D. A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity. Cell Death Discov., 2020, 6(1), 20.
[http://dx.doi.org/10.1038/s41420-020-0258-3] [PMID: 32337072]
[15]
Masoud, G.N.; Li, W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm. Sin. B, 2015, 5(5), 378-389.
[http://dx.doi.org/10.1016/j.apsb.2015.05.007] [PMID: 26579469]
[16]
Jun, J.C.; Rathore, A.; Younas, H.; Gilkes, D.; Polotsky, V.Y. Hypoxia-inducible factors and cancer. Curr. Sleep Med. Rep., 2017, 3(1), 1-10.
[http://dx.doi.org/10.1007/s40675-017-0062-7] [PMID: 28944164]
[17]
Le, Q-T.; Courter, D. Clinical biomarkers for hypoxia targeting. Cancer Metastasis Rev., 2008, 27(3), 351-362.
[http://dx.doi.org/10.1007/s10555-008-9144-9] [PMID: 18483785]
[18]
Semenza, G.L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev., 2010, 20(1), 51-56.
[http://dx.doi.org/10.1016/j.gde.2009.10.009] [PMID: 19942427]
[19]
Cui, X.G.; Han, Z.T.; He, S.H.; Wu, X.D.; Chen, T.R.; Shao, C.H.; Chen, D.L.; Su, N.; Chen, Y.M.; Wang, T.; Wang, J.; Song, D.W.; Yan, W.J.; Yang, X.H.; Liu, T.; Wei, H.F.; Xiao, J. HIF1/2α mediates hypoxia-induced LDHA expression in human pancreatic cancer cells. Oncotarget, 2017, 8(15), 24840-24852.
[http://dx.doi.org/10.18632/oncotarget.15266] [PMID: 28193910]
[20]
Gabison, E.E.; Hoang-Xuan, T.; Mauviel, A.; Menashi, S. EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. Biochimie, 2005, 87(3-4), 361-368.
[http://dx.doi.org/10.1016/j.biochi.2004.09.023] [PMID: 15781323]
[21]
Lian, C.; Guo, Y.; Zhang, J.; Chen, X.; Peng, C. Targeting CD147 is a novel strategy for antitumor therapy. Curr. Pharm. Des., 2017, 23(29), 4410-4421.
[http://dx.doi.org/10.2174/1381612823666170710144759] [PMID: 28699528]
[22]
Landras, A.; Reger de Moura, C.; Jouenne, F.; Lebbe, C.; Menashi, S.; Mourah, S. CD147 is a promising target of tumor progression and a prognostic biomarker. Cancers, 2019, 11(11), E1803.
[http://dx.doi.org/10.3390/cancers11111803] [PMID: 31744072]
[23]
Yu, B.; Zhang, Y.; Wu, K.; Wang, L.; Jiang, Y.; Chen, W.; Yan, M. CD147 promotes progression of head and neck squamous cell carcinoma via NF-kappa B signaling. J. Cell. Mol. Med., 2019, 23(2), 954-966.
[http://dx.doi.org/10.1111/jcmm.13996] [PMID: 30421493]
[24]
Saha, S.K.; Islam, S.M.R.; Abdullah-Al-Wadud, M.; Islam, S.; Ali, F.; Park, K.S. Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. J. Clin. Med., 2019, 8(3), 355.
[http://dx.doi.org/10.3390/jcm8030355] [PMID: 30871151]
[25]
Li, X.; Zhang, Y.; Ma, W.; Fu, Q.; Liu, J.; Yin, G.; Chen, P.; Dai, D.; Chen, W.; Qi, L.; Yu, X.; Xu, W. Enhanced glucose metabolism mediated by CD147 contributes to immunosuppression in hepatocellular carcinoma. Cancer Immunol. Immunother., 2020, 69(4), 535-548.
[http://dx.doi.org/10.1007/s00262-019-02457-y] [PMID: 31965268]
[26]
Matés, J.M.; Di Paola, F.J.; Campos-Sandoval, J.A.; Mazurek, S.; Márquez, J. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin. Cell Dev. Biol., 2020, 98, 34-43.
[http://dx.doi.org/10.1016/j.semcdb.2019.05.012] [PMID: 31100352]
[27]
Swartz, J.E.; Pothen, A.J.; Stegeman, I.; Willems, S.M.; Grolman, W. Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: A systematic review. Cancer Med., 2015, 4(7), 1101-1116.
[http://dx.doi.org/10.1002/cam4.460] [PMID: 25919147]
[28]
Xin, X.; Zeng, X.; Gu, H.; Li, M.; Tan, H.; Jin, Z.; Hua, T.; Shi, R.; Wang, H. CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis. Sci. Rep., 2016, 6, 32804.
[http://dx.doi.org/10.1038/srep32804] [PMID: 27608940]
[29]
Cluntun, A.A.; Lukey, M.J.; Cerione, R.A.; Locasale, J.W. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer, 2017, 3(3), 169-180.
[http://dx.doi.org/10.1016/j.trecan.2017.01.005] [PMID: 28393116]
[30]
Li, B.; Cao, Y.; Meng, G.; Qian, L.; Xu, T.; Yan, C.; Luo, O.; Wang, S.; Wei, J.; Ding, Y.; Yu, D. Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine, 2019, 39, 239-254.
[http://dx.doi.org/10.1016/j.ebiom.2018.11.063] [PMID: 30555042]
[31]
Kim, J.Y.; Heo, S-H.; Choi, S.K.; Song, I.H.; Park, I.A.; Kim, Y-A.; Park, H.S.; Park, S.Y.; Bang, W.S.; Gong, G.; Lee, H.J. Glutaminase expression is a poor prognostic factor in node-positive triple-negative breast cancer patients with a high level of tumor-infiltrating lymphocytes. Virchows Arch., 2017, 470(4), 381-389.
[http://dx.doi.org/10.1007/s00428-017-2083-5] [PMID: 28185053]
[32]
Huang, F.; Zhang, Q.; Ma, H.; Lv, Q.; Zhang, T. Expression of glutaminase is upregulated in colorectal cancer and of clinical significance. Int. J. Clin. Exp. Pathol., 2014, 7(3), 1093-1100.
[PMID: 24696726]
[33]
Matre, P.; Velez, J.; Jacamo, R.; Qi, Y.; Su, X.; Cai, T.; Chan, S.M.; Lodi, A.; Sweeney, S.R.; Ma, H.; Davis, R.E.; Baran, N.; Haferlach, T.; Su, X.; Flores, E.R.; Gonzalez, D.; Konoplev, S.; Samudio, I.; DiNardo, C.; Majeti, R.; Schimmer, A.D.; Li, W.; Wang, T.; Tiziani, S.; Konopleva, M. Inhibiting glutaminase in acute myeloid leukemia: Metabolic dependency of selected AML subtypes. Oncotarget, 2016, 7(48), 79722-79735.
[http://dx.doi.org/10.18632/oncotarget.12944] [PMID: 27806325]
[34]
Szeliga, M.; Bogacińska-Karaś, M.; Różycka, A.; Hilgier, W.; Marquez, J.; Albrecht, J. Silencing of GLS and overexpression of GLS2 genes cooperate in decreasing the proliferation and viability of glioblastoma cells. Tumour Biol., 2014, 35(3), 1855-1862.
[http://dx.doi.org/10.1007/s13277-013-1247-4] [PMID: 24096582]
[35]
Dias, M.M.; Adamoski, D.; Dos Reis, L.M.; Ascenção, C.F.R.; de Oliveira, K.R.S.; Mafra, A.C.P.; da Silva Bastos, A.C.; Quintero, M.; de G Cassago, C.; Ferreira, I.M.; Fidelis, C.H.V.; Rocco, S.A.; Bajgelman, M.C.; Stine, Z.; Berindan-Neagoe, I.; Calin, G.A.; Ambrosio, A.L.B.; Dias, S.M.G. GLS2 is protumorigenic in breast cancers. Oncogene, 2020, 39(3), 690-702.
[http://dx.doi.org/10.1038/s41388-019-1007-z] [PMID: 31541193]
[36]
Pérez-Gómez, C.; Campos-Sandoval, J.A.; Alonso, F.J.; Segura, J.A.; Manzanares, E.; Ruiz-Sánchez, P.; González, M.E.; Márquez, J.; Matés, J.M. Co-expression of glutaminase K and L isoenzymes in human tumour cells. Biochem. J., 2005, 386(Pt 3), 535-542.
[http://dx.doi.org/10.1042/BJ20040996] [PMID: 15496140]
[37]
Yu, D.; Shi, X.; Meng, G.; Chen, J.; Yan, C.; Jiang, Y.; Wei, J.; Ding, Y. Kidney-type glutaminase (GLS1) is a biomarker for pathologic diagnosis and prognosis of hepatocellular carcinoma. Oncotarget, 2015, 6(10), 7619-7631.
[http://dx.doi.org/10.18632/oncotarget.3196] [PMID: 25844758]
[38]
Yuneva, M.O.; Fan, T.W.; Allen, T.D.; Higashi, R.M.; Ferraris, D.V.; Tsukamoto, T.; Matés, J.M.; Alonso, F.J.; Wang, C.; Seo, Y.; Chen, X.; Bishop, J.M. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab., 2012, 15(2), 157-170.
[http://dx.doi.org/10.1016/j.cmet.2011.12.015] [PMID: 22326218]
[39]
Kirk, P.; Wilson, M.C.; Heddle, C.; Brown, M.H.; Barclay, A.N.; Halestrap, A.P. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J., 2000, 19(15), 3896-3904.
[http://dx.doi.org/10.1093/emboj/19.15.3896] [PMID: 10921872]
[40]
Schneiderhan, W.; Scheler, M.; Holzmann, K.H.; Marx, M.; Gschwend, J.E.; Bucholz, M.; Gress, T.M.; Seufferlein, T.; Adler, G.; Oswald, F. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut, 2009, 58(10), 1391-1398.
[http://dx.doi.org/10.1136/gut.2009.181412] [PMID: 19505879]
[41]
de la Cruz-López, K.G.; Castro-Muñoz, L.J.; Reyes-Hernández, D.O.; García-Carrancá, A.; Manzo-Merino, J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front. Oncol., 2019, 9(1143), 1143.
[http://dx.doi.org/10.3389/fonc.2019.01143] [PMID: 31737570]
[42]
Pérez-Escuredo, J.; Dadhich, R.K.; Dhup, S.; Cacace, A.; Van Hée, V.F.; De Saedeleer, C.J.; Sboarina, M.; Rodriguez, F.; Fontenille, M-J.; Brisson, L.; Porporato, P.E.; Sonveaux, P. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle, 2016, 15(1), 72-83.
[http://dx.doi.org/10.1080/15384101.2015.1120930] [PMID: 26636483]
[43]
Jing, X.; Yang, F.; Shao, C.; Wei, K.; Xie, M.; Shen, H.; Shu, Y. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol. Cancer, 2019, 18(1), 157.
[http://dx.doi.org/10.1186/s12943-019-1089-9] [PMID: 31711497]
[44]
Brown, J.M. Tumor hypoxia in cancer therapy.Methods Enzymol., 2007, 435, 295-321.
[45]
Al Tameemi, W.; Dale, T.P.; Al-Jumaily, R.M.K.; Forsyth, N.R. Hypoxia-modified cancer cell metabolism. Front. Cell Dev. Biol., 2019, 7, 4.
[http://dx.doi.org/10.3389/fcell.2019.00004] [PMID: 30761299]
[46]
Lai, S.Y.; Rubin-Grandis, J. HIF-1 modulates head and neck cancer progression and invasion. Otolaryngol. Head Neck Surg., 2004, 131(2), 112.
[http://dx.doi.org/10.1016/j.otohns.2004.06.159]
[47]
Basheer, H.A.; Pakanavicius, E.; Cooper, P.A.; Shnyder, S.D.; Martin, L.; Hunter, K.D.; Vinader, V.; Afarinkia, K. Hypoxia modulates CCR7 expression in head and neck cancers. Oral Oncol., 2018, 80, 64-73.
[http://dx.doi.org/10.1016/j.oraloncology.2018.03.014] [PMID: 29706190]
[48]
Ban, H. S.; Kim, B.-K.; Lee, H.; Kim, H. M.; Harmalkar, D.; Nam, M.; Park, S.-K.; Lee, K.; Park, J.-T.; Kim, I.; Lee, K.; Hwang, G.-S.; Won, M. The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis., 2017, 8(6), e2843-e.
[http://dx.doi.org/10.1038/cddis.2017.235]
[49]
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer, 2003, 3(10), 721-732.
[http://dx.doi.org/10.1038/nrc1187] [PMID: 13130303]

Rights & Permissions Print Cite
Article Metrics
30
1
© 2024 Bentham Science Publishers | Privacy Policy