MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

Haowei Zhang; Qixin Li; Xiaolong Guo; Hong Wu; Chenhao Hu; Gaixia Liu; Tianyu Yu; Xiake Hu; Quanpeng Qiu; Gang Guo; Junjun She; Yinnan Chen

doi:10.1016/j.jpha.2024.02.004

Volume 14 Issue 6

Jun. 2024

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Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(6): 100950

Haowei Zhang, Qixin Li, Xiaolong Guo, Hong Wu, Chenhao Hu, Gaixia Liu, Tianyu Yu, Xiake Hu, Quanpeng Qiu, Gang Guo, Junjun She, Yinnan Chen. MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100950. doi: 10.1016/j.jpha.2024.02.004

Citation:

Haowei Zhang, Qixin Li, Xiaolong Guo, Hong Wu, Chenhao Hu, Gaixia Liu, Tianyu Yu, Xiake Hu, Quanpeng Qiu, Gang Guo, Junjun She, Yinnan Chen. MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100950. doi: 10.1016/j.jpha.2024.02.004

Citation:

Haowei Zhang, Qixin Li, Xiaolong Guo, Hong Wu, Chenhao Hu, Gaixia Liu, Tianyu Yu, Xiake Hu, Quanpeng Qiu, Gang Guo, Junjun She, Yinnan Chen. MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(6): 100950. doi: 10.1016/j.jpha.2024.02.004

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MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

doi: 10.1016/j.jpha.2024.02.004

Haowei Zhang^a,b,
Qixin Li^a,b,
Xiaolong Guo^b,
Hong Wu^a,
Chenhao Hu^a,c,
Gaixia Liu^a,b,
Tianyu Yu^a,b,
Xiake Hu^a,b,
Quanpeng Qiu^a,b,
Gang Guo^b,c,
Junjun She^{a,b,c
,
,},
Yinnan Chen^{b,c
,
,}

a. Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
b. Center for Gut Microbiome Research, Med-X Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China;
c. Department of High Talent, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China

Funds:

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos.: 82003807 and 82173394), the Shaanxi Province Science Foundation, China (Grant No.: 2023-GHZD-19), the Medical Foundation-Clinical Integration Program of Xi'an Jiaotong University, China (Grant No.: YXJLRH2022043), and the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation, China (Grant No.: xzy012023104).

Received Date: Sep. 13, 2023
Accepted Date: Feb. 07, 2024
Rev Recd Date: Jan. 31, 2024
Publish Date: Feb. 10, 2024

Abstract

Abstract

Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer (CRC). Cisplatin (DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair. Among the elements that lead to DDP resistance, O⁶-methylguanine (O⁶-MG)-DNA-methyltransferase (MGMT), a DNA-repair enzyme, performs a quintessential role. In this study, we clarify the significant involvement of MGMT in conferring DDP resistance in CRC, elucidating the underlying mechanism of the regulatory actions of MGMT. A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study, and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo. Conversely, in cancer cells, MGMT overexpression abolishes their sensitivity to DDP treatment. Mechanistically, the interaction between MGMT and cyclin dependent kinase 1 (CDK1) inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1. Meanwhile, to achieve nonhomologous end joining, MGMT interacts with XRCC6 to resist chemotherapy drugs. Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation, and several Wnt inhibitors can repress drug-resistant cells. In summary, our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.
- Colorectal cancer,
- MGMT,
- Chemotherapy resistance,
- Slow-cycling cells,
- Nonhomologous end joining,
- Wnt pathway

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References(39)

References

[1]	E.J. Kuipers, W.M. Grady, D. Lieberman, et al., Colorectal cancer, Nat. Rev. Dis. Primers 1(2015), 15065.
[2]	Z.H. Siddik, Cisplatin:Mode of cytotoxic action and molecular basis of resistance, Oncogene 22(2003)7265-7279.
[3]	L. Galluzzi, L. Senovilla, I. Vitale, et al., Molecular mechanisms of cisplatin resistance, Oncogene 31(2012)1869-1883.
[4]	C. Passirani, A. Vessieres, G. La Regina, et al., Modulating undruggable targets to overcome cancer therapy resistance, Drug Resist. Updat. 60(2022), 100788.
[5]	S.K. Rehman, J. Haynes, E. Collignon, et al., Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy, Cell 184(2021)226-242.e21.
[6]	S.V. Sharma, D.Y. Lee, B. Li, et al., A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations, Cell 141(2010)69-80.
[7]	B.B. Liau, C. Sievers, L.K. Donohue, et al., Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance, Cell Stem Cell 20(2017)233-246.e7.
[8]	I. Puig, S.P. Tenbaum, I. Chicote, et al., TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence, J. Clin. Invest. 128(2018)3887-3905.
[9]	M. Malumbres, Cyclin-dependent kinases, Genome Biol. 15(2014), 122.
[10]	N. Rhind, P. Russell, Signaling pathways that regulate cell division, Cold Spring Harb. Perspect. Biol. 4(2012), a005942.
[11]	C. Trovesi, N. Manfrini, M. Falcettoni, et al., Regulation of the DNA damage response by cyclin-dependent kinases, J. Mol. Biol. 425(2013)4756-4766.
[12]	J.M. Suski, N. Ratnayeke, M. Braun, et al., CDC7-independent G1/S transition revealed by targeted protein degradation, Nature 605(2022)357-365.
[13]	L. Sisinni, F. Maddalena, V. Condelli, et al., TRAP1 controls cell cycle G2-M transition through the regulation of CDK1 and MAD2 expression/ubiquitination, J. Pathol. 243(2017)123-134.
[14]	A. Recasens, L. Munoz, Targeting cancer cell dormancy, Trends Pharmacol. Sci. 40(2019)128-141.
[15]	S.H. Chen, W.T. Huang, W. Kao, et al., O6-methylguanine-DNA methyltransferase modulates cisplatin-induced DNA double-strand breaks by targeting the homologous recombination pathway in nasopharyngeal carcinoma, J. Biomed. Sci. 28(2021), 2.
[16]	R.R. White, J. Vijg, Do DNA double-strand breaks drive aging?Mol. Cell 63(2016)729-738.
[17]	R. Scully, A. Panday, R. Elango, et al., DNA double-strand break repair-pathway choice in somatic mammalian cells, Nat. Rev. Mol. Cell Biol. 20(2019)698-714.
[18]	E. Convery, E.K. Shin, Q. Ding, et al., Inhibition of homologous recombination by variants of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), Proc. Natl. Acad. Sci. U S A 102(2005)1345-1350.
[19]	D. Ghosh, S.C. Raghavan, Nonhomologous end joining:New accessory factors fine tune the machinery, Trends Genet. 37(2021)582-599.
[20]	L.S. Symington, J. Gautier, Double-strand break end resection and repair pathway choice, Annu. Rev. Genet. 45(2011)247-271.
[21]	W. Yu, L. Zhang, Q. Wei, et al., O⁶-methylguanine-DNA methyltransferase (MGMT):Challenges and new opportunities in glioma chemotherapy, Front. Oncol. 9(2020), 1547.
[22]	S.A. Abdellatief, A.A. Galal, S.M. Farouk, et al., Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity:A biochemical, histopathological, and immunohistochemical study, Biomed. Pharmacother. 86(2017)482-491.
[23]	B.S. Moon, M. Cai, G. Lee, et al., Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma, J. Clin. Invest. 130(2020)5782-5799.
[24]	D.S. Malley, R.A. Hamoudi, S. Kocialkowski, et al., A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts, Acta Neuropathol. 121(2011)651-661.
[25]	M. Wickstrom, C. Dyberg, J. Milosevic, et al., Wnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance, Nat. Commun. 6(2015), 8904.
[26]	J. Raisch, A. Cote-Biron, M.J. Langlois, et al., Unveiling the roles of low-density lipoprotein receptor-related protein 6 in intestinal homeostasis, regeneration and oncogenesis, Cells 10(2021), 1792.
[27]	G. Emons, M. Spitzner, S. Reineke, et al., Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/β-catenin signaling, Mol. Cancer Res. 15(2017)1481-1490.
[28]	J. Wang, H. Min, B. Hu, et al., Guanylate-binding protein-2 inhibits colorectal cancer cell growth and increases the sensitivity to paclitaxel of paclitaxel-resistant colorectal cancer cells by interfering Wnt signaling, J. Cell. Biochem. 121(2020)1250-1259.
[29]	N. Kugimiya, A. Nishimoto, T. Hosoyama, et al., The c-MYC-ABCB5 axis plays a pivotal role in 5-fluorouracil resistance in human colon cancer cells, J. Cell. Mol. Med. 19(2015)1569-1581.
[30]	R. Patro, G. Duggal, M.I. Love, et al., Salmon provides fast and bias-aware quantification of transcript expression, Nat. Methods 14(2017)417-419.
[31]	Y. Zhou, B. Zhou, L. Pache, et al., Metascape provides a biologist-oriented resource for the analysis of systems-level datasets, Nat. Commun. 10(2019), 1523.
[32]	M.I. Love, W. Huber, S. Anders, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2, Genome Biol. 15(2014), 550.
[33]	B. Kaina, M. Christmann, S. Naumann, et al., MGMT:Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents, DNA Repair 6(2007)1079-1099.
[34]	T. Iyama, D.M. Wilson 3rd, DNA repair mechanisms in dividing and non-dividing cells, DNA Repair 12(2013)620-636.
[35]	A.E. Pegg, Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools, Chem. Res. Toxicol. 24(2011)618-639.
[36]	K.A. van Nifterik, J. van den Berg, W.F. van der Meide, et al., Absence of the MGMT protein as well as methylation of the MGMT promoter predict the sensitivity for temozolomide, Br. J. Cancer 103(2010)29-35.
[37]	R. Sancho, A.S. Nateri, A.G. de Vinuesa, et al., JNK signalling modulates intestinal homeostasis and tumourigenesis in mice, EMBO J. 28(2009)1843-1854.
[38]	K.H. Goss, J. Groden, Biology of the adenomatous polyposis coli tumor suppressor, J. Clin. Oncol. 18(2000)1967-1979.
[39]	S. Munemitsu, I. Albert, B. Souza, et al., Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein, Proc. Natl. Acad. Sci. U S A 92(1995)3046-3050.