PKM2 Expression As Biomarker for Resistance to Oxaliplatin-Based Chemotherapy in Colorectal Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2020 Jul 30

PMID 32722474

Citations 13

Authors

Maria Sfakianaki

Chara Papadaki

Maria Tzardi

Maria Trypaki

Stavroula Manolakou

Ippokratis Messaritakis

Zenia Saridaki

Elias Athanasakis

Dimitrios Mavroudis

John Tsiaoussis

Nikolaos Gouvas

John Souglakos

Affiliations

Soon will be listed here.

Abstract

The purpose of the current study is to investigate the prognostic significance of M2 isoform of pyruvate kinase (PKM2) expression loss in patients with operable colon cancer (CC). Two hundred sixty-two specimens from patients with stage-III or high-risk stage-II CC (group-A) treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy (FOLFOX), 118 specimens from metastatic CC patients (group-B) treated with FOLFOX, and 104 metastatic CC patients (group-C) treated with irinotecan-based chemotherapy were analyzed for , and mRNA expression, as well as exon2 and mutations. High mRNA expression was correlated with left-sided located primaries ( = 0.001, group-A; = 0.003, group-B; = 0.001, group-C), high-grade tumors ( = 0.001, group-A; = 0.017, group-B; = 0.021, group-C), microsatellite-stable tumors ( < 0.001, group-A), pericolic lymph nodes involvement ( = 0.018, group-A), and mRNA expression ( = 0.002, group-A; = 0.008, group-B; = 0.006, group-C). High mRNA expression was correlated with significantly lower disease free survival (DFS) ( = 0.002) and overall survival (OS) ( = 0.001) in the group-A. Similarly, mRNA expression was associated with significantly decreased progression free survival (PFS) ( = 0.001) and OS ( = 0.001) in group-B. On the contrary, no significant association for the mRNA expression has been observed with either PFS ( = 0.612) or OS ( = 0.517) in group-C. To conclude, the current study provides evidence for the prediction of mRNA expression oxaliplatin-based treatment resistance.

Citing Articles

Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy.

Tao H, Zhong X, Zeng A, Song L Front Immunol. 2023; 14:1208870.

PMID: 37564659 PMC: 10411982. DOI: 10.3389/fimmu.2023.1208870.

In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer.

Lee C, Lee A, Wei P, Liu Y, Chang Y, Huang C Sci Rep. 2023; 13(1):4366.

PMID: 36927770 PMC: 10020571. DOI: 10.1038/s41598-023-31331-2.

Modulating Glycolysis to Improve Cancer Therapy.

Chelakkot C, Chelakkot V, Shin Y, Song K Int J Mol Sci. 2023; 24(3).

PMID: 36768924 PMC: 9916680. DOI: 10.3390/ijms24032606.

Evaluation of Microsatellite Instability Molecular Analysis versus Immuno-Histochemical Interpretation in Malignant Neoplasms with Different Localizations.

Sfakianaki M, Tzardi M, Tsantaki K, Koutoulaki C, Messaritakis I, Datseri G Cancers (Basel). 2023; 15(2).

PMID: 36672302 PMC: 9856558. DOI: 10.3390/cancers15020353.

Investigation of Microbial Translocation, and Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients.

Messaritakis I, Koulouridi A, Boukla E, Sfakianaki M, Vogiatzoglou K, Karagianni M Cancers (Basel). 2022; 14(18).

PMID: 36139567 PMC: 9496848. DOI: 10.3390/cancers14184407.

References

Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W . Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature. 2011; 480(7375):118-22. PMC: 3235705. DOI: 10.1038/nature10598. View

Cui R, Shi X . Expression of pyruvate kinase M2 in human colorectal cancer and its prognostic value. Int J Clin Exp Pathol. 2015; 8(9):11393-9. PMC: 4637681. View

Zhang H, Zhang F, Li H, Liu Y, Du G, Huang Y . Tanshinone ⅡA inhibits human esophageal cancer cell growth through miR-122-mediated PKM2 down-regulation. Arch Biochem Biophys. 2016; 598:50-6. DOI: 10.1016/j.abb.2016.03.031. View

Jiang Y, Wang Y, Wang T, Hawke D, Zheng Y, Li X . PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat Commun. 2014; 5:5566. PMC: 4259466. DOI: 10.1038/ncomms6566. View

Koss K, Maxton D, Jankowski J . Faecal dimeric M2 pyruvate kinase in colorectal cancer and polyps correlates with tumour staging and surgical intervention. Colorectal Dis. 2007; 10(3):244-8. DOI: 10.1111/j.1463-1318.2007.01334.x. View

Martinez-Balibrea E, Plasencia C, Gines A, Martinez-Cardus A, Musulen E, Aguilera R . A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines. Mol Cancer Ther. 2009; 8(4):771-8. DOI: 10.1158/1535-7163.MCT-08-0882. View

Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M . Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009; 101(3):465-72. PMC: 2720232. DOI: 10.1038/sj.bjc.6605164. View

Cushman-Vokoun A, Stover D, Zhao Z, Koehler E, Berlin J, Vnencak-Jones C . Clinical utility of KRAS and BRAF mutations in a cohort of patients with colorectal neoplasms submitted for microsatellite instability testing. Clin Colorectal Cancer. 2013; 12(3):168-78. PMC: 4090139. DOI: 10.1016/j.clcc.2013.04.005. View

Zhou C, Li X, Sun H, Zhang B, Han Y, Jiang Y . Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells. IUBMB Life. 2012; 64(9):775-82. DOI: 10.1002/iub.1066. View

10.

He X, Du S, Lei T, Li X, Liu Y, Wang H . PKM2 in carcinogenesis and oncotherapy. Oncotarget. 2018; 8(66):110656-110670. PMC: 5746412. DOI: 10.18632/oncotarget.22529. View

11.

Christofk H, Vander Heiden M, Harris M, Ramanathan A, Gerszten R, Wei R . The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008; 452(7184):230-3. DOI: 10.1038/nature06734. View

12.

Li S, Ye F, Cai W, Hu H, Hu P, Ren H . Quantitative proteome analysis of multidrug resistance in human ovarian cancer cell line. J Cell Biochem. 2010; 109(4):625-33. DOI: 10.1002/jcb.22413. View

13.

Yoo B, Ku J, Hong S, Shin Y, Park S, Kim H . Decreased pyruvate kinase M2 activity linked to cisplatin resistance in human gastric carcinoma cell lines. Int J Cancer. 2003; 108(4):532-9. DOI: 10.1002/ijc.11604. View

14.

Liberti M, Locasale J . The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci. 2016; 41(3):211-218. PMC: 4783224. DOI: 10.1016/j.tibs.2015.12.001. View

15.

Fitzmaurice C, Akinyemiju T, Al Lami F, Alam T, Alizadeh-Navaei R, Allen C . Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2018; 4(11):1553-1568. PMC: 6248091. DOI: 10.1001/jamaoncol.2018.2706. View

16.

Vogelstein B, Kinzler K . Cancer genes and the pathways they control. Nat Med. 2004; 10(8):789-99. DOI: 10.1038/nm1087. View

17.

Sfakianaki M, Papadaki C, Tzardi M, Trypaki M, Alam S, Lagoudaki E . Loss of LKB1 Protein Expression Correlates with Increased Risk of Recurrence and Death in Patients with Resected, Stage II or III Colon Cancer. Cancer Res Treat. 2019; 51(4):1518-1526. PMC: 6790836. DOI: 10.4143/crt.2019.008. View

18.

Zhang X, He C, He C, Chen B, Liu Y, Kong M . Nuclear PKM2 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Pathol Res Pract. 2013; 209(8):510-5. DOI: 10.1016/j.prp.2013.06.005. View

19.

Martinez-Cardus A, Martinez-Balibrea E, Bandres E, Malumbres R, Gines A, Luis Manzano J . Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer. Mol Cancer Ther. 2009; 8(1):194-202. DOI: 10.1158/1535-7163.MCT-08-0659. View

20.

Papadaki C, Sfakianaki M, Lagoudaki E, Giagkas G, Ioannidis G, Trypaki M . PKM2 as a biomarker for chemosensitivity to front-line platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer. Br J Cancer. 2014; 111(9):1757-64. PMC: 4453739. DOI: 10.1038/bjc.2014.492. View