GCDH contributes to better outcome and acts on chemoresistance and immune exclusion in cervical cancer

Aim: Cervical cancer is a major health problem in women and its genetic culprit remains inclusive. The authors aim to evaluate the role of glutaryl-CoA dehydrogenase (GCDH) in cervical cancer. Materials and Methods: Clinicopathological attribution of GCDH was queried in silico using the human cancer genome atlas project (TCGA) and HPA database. In vitro studies using cell lines and nude mice were used to examine the therapeutic potential of targeting GCDH. Results: GCDH expression was significantly higher in cancer tissue compared with normal cervical tissue. Cervical cancer patients with overexpressed GCDH had significantly better overall survival. Functional annotation indicated enrichment in cell-cycle regulatory pathway. Knockdown (KD) and overexpression (OE) of GCDH-induced increased and decreased proliferation, respectively. Similar results were also obtained in cell-cycle arrest, invasion, migration, and colony formation assays, but having no effect on cell apoptosis. To understand the selection advantage of GCHD-overexpressed cases, the authors analyzed immunological profile in silico. Expression of GCDH correlated with that of IDO2, which was significantly associated with decreased immunity. GCDH-KD-induced decreased expression of IDO2, which also led to decreased kynurenine and tryptophan in culturing media. GCDH-OE promoted chemoresistance in cervical cancer cells due to cell-cycle arrest. GCDH-OE also significantly inhibited tumor growth in vivo yet showed partial resistance to chemotherapy, with increased level of IDO2 expression. Conclusion: GCDH is overexpressed in cervical cancer and represents a less aggressive phenotype of disease, which is also characterized with increased chemoresistance and immune exclusion. Inhibition of IDO2 could be of therapeutic potential.

Cervical cancer; GCDH; Chemoresistance; Immune exclusion

[1] Siegel R.L., Miller K.D., Jemal A., “Cancer statistics, 2018”. CA Cancer J Clin., 2018, 68, 7.

[2] Tran N.P, Hung C.F, Roden R., Wu T.C.: “Control of HPV infection and related cancer through vaccination”. Recent Results Cancer Res., 2014, 193, 149.

[3] Dunne E.F., Park I.U.: “HPV and HPV-associated diseases”. Infect. Dis. Clin. North Am., 2013, 27, 765.

[4] Razzaghi H., Saraiya M., Thompson T.D., Henley S.J., Viens L., Wilson R.: “Five-year relative survival for human papillomavirus-associated cancer sites”. Cancer, 2018, 124, 203.

[5] Burk R.D., Chen Z., Saller C., Tarvin K., Carvalho A.L., Scapulatempo-Neto C., et al.: “Integrated genomic and molecular characterization of cervical cancer”. Nature, 2017, 543, 378.

[6] Keyser B., Mühlhausen C., Dickmanns A., Christensen E., Muschol N., Ullrich K., et al.: “Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)”. Hum. Mol. Genet., 2008, 17, 3854.

[7] Bjelić S., Wieninger S., Jelesarov I., Karshikoff A.: “Electrostatic contribution to the thermodynamic and kinetic stability of the homotrimeric coiled coil Lpp-56: A computational study”. Proteins, 2008, 70, 810.

[8] Oh H.R., An C.H., Yoo N.J., Lee S.H.: “Somatic mutations of amino acid metabolism-related genes in gastric and colorectal cancers and their regional heterogeneity—a short report”. Cell Oncol. (Dordr.), 2014, 37, 455.

[9] Gao J., Aksoy B.A., Dogrusoz U., Dresdner G., Gross B., Sumer S.O., et al.: “Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal”. Sci. Signal., 2013, 6, l1.

[10] Cerami E., Gao J., Dogrusoz U., Gross B.E., Sumer S.O., Aksoy B.A., et al.: “The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data”. Cancer Discov., 2012, 2, 401.

[11] Xie C., Mao X., Huang J., Ding Y., Wu J., Dong S., et al.: “KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases”. Nucleic Acids Res., 2011, 39, W316.

[12] Wu J., Mao X., Cai T., Luo J., Wei L., “KOBAS server: a web-based platform for automated annotation and pathway identification”. Nucleic Acids Res., 2006, 34, W720.

[13] Uhlén M., Fagerberg L., Hallström B.M., Lindskog C., Oksvold P., Mardinoglu A., et al.: “Proteomics. Tissue-based map of the human proteome”. Science, 2015, 347, 1260419.

[14] Uhlen M., Oksvold P., Fagerberg L., Lundberg E., Jonasson K., Forsberg M., et al.: “Towards a knowledge-based Human Protein Atlas”. Nat Biotechnol., 2010, 28, 1248.

[15] Uhlén M., Björling E., Agaton C., Szigyarto C.A., Amini B., Andersen E., et al.: “A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics”. 2005, 4, 1920.

[16] Pontén F., Jirström K., Uhlen M., “The Human Protein Atlas—a tool for pathology”. J. Pathol., 2008, 216, 387.

[17] Feng C.C., Ding Q., Zhang Y.F., Jiang H.W., Wen H., Wang P.H., et al.: “Pigment epithelium-derived factor expression is down-regulated in bladder tumors and correlates with vascular endothelial growth factor and matrix metalloproteinase-9”. Int. Urol. Nephrol., 2011, 43, 383.

[18] Feng C.C., Wang P.H., Ding Q., Guan M., Zhang Y.F., Jiang H.W., et al.: “Expression of pigment epithelium-derived factor and tumor necrosis factor-α is correlated in bladder tumor and is related to tumor angiogenesis”. Urol. Oncol., 2013, 31, 241.

[19] Li B., Severson E., Pignon J.C., Zhao H., Li T., Novak J., et al.: “Comprehensive analyses of tumor immunity: implications for cancer immunotherapy”. Genome Biol., 2016, 17, 174.

[20] Liu S., Jiang H., Wen H., Ding Q., Feng C., “Knockdown of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) enhances tumorigenesis both in vivo and in vitro in bladder cancer”. Oncol. Rep., 2018, 39, 2127.

[21] Jinushi M., Chiba S., Yoshiyama H., Masutomi K., Kinoshita I., Dosaka-Akita H., et al.: “Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells”. Proc. Natl. Acad. Sci., USA, 2011, 108, 12425.

[22] Li B., Severson E., Pignon J.C., Zhao H., Li T., Novak J., et al.: “The indoleamine-2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan upregulates IDO1 in human cancer cells”. PLoS One, 2011, 6, e19823.

[23] Wiltshire T., Senft J., Wang Y., Konat G.W., Wenger S.L., Reed E., et al.: “BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven”. Mol. Pharmacol., 2007, 71, 1051.

[24] Miwa S., Yano S., Kimura H., Yamamoto M., Toneri M., Matsumoto Y., et al.: “Cell-cycle fate-monitoring distinguishes individual chemosensitive and chemoresistant cancer cells in drug-treated heterogeneous populations demonstrated by real-time FUCCI imaging”. Cell Cycle, 2015, 14, 621.

[25] Brown J.A., Yonekubo Y., Hanson N., Sastre-Perona A., Basin A., Rytlewski J.A., et al.: “TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma”. Cell Stem Cell. 2017, 21, 650.e8.