PKM2 regulates proliferation and apoptosis through the Hippo pathway in oral tongue squamous cell carcinoma

Luo,Jia; Zhang,Lei; Guo,Lijuan; Yang,Sen

doi:10.3892/ol.2021.12722

PKM2 regulates proliferation and apoptosis through the Hippo pathway in oral tongue squamous cell carcinoma

Authors:
- Jia Luo
- Lei Zhang
- Lijuan Guo
- Sen Yang
View Affiliations

Affiliations: Department of Oral and Maxillofacial Surgery, Suining Central Hospital, Suining, Sichuan 629000, P.R. China, Department of Endodontics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Medical Beauty Department, Suining Central Hospital, Suining, Sichuan 629000, P.R. China
Published online on: April 11, 2021 https://doi.org/10.3892/ol.2021.12722
Article Number: 461
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oral tongue squamous cell carcinoma (OTSCC) is a highly malignant type of tumor. The 5‑year survival rate of patients with advanced tongue squamous cell carcinoma is only ~50%. Pyruvate kinase M2 (PKM2) is the key rate‑limiting enzyme of glycolysis, maintaining the Warburg effect in tumor cells. The present study aimed to investigate the relationship between PKM2 expression and the poor prognosis of patients with OTSCC and to determine oral squamous carcinoma tumor cell proliferation and apoptosis. Reverse transcription‑quantitative (RT‑q) PCR, western blotting and immunohistochemistry were used to analyze the expression levels of PKM2 in OTSCC, and the clinicopathological characteristics and prognosis of patients with OTSCC were further analyzed by statistical analysis. The results from RT‑qPCR and immunohistochemistry demonstrated that PKM2 was upregulated in OTSCC tissues and highly expressed in advanced stage OTSCC tissues compared with paired adjacent tissues and lower stage OTSCC tissues. Patients with OTSCC and high PKM2 expression had shorter overall survival (OS) compared with those with low PKM2 expression. Furthermore, high expression of PKM2 was significantly associated with Tumor‑Node‑Metastasis (TNM) stage. TNM stage and PKM2 expression were independent predictive factors for OS in patients with OTSCC. In addition, PKM2 knockdown inhibited the proliferation and increased the apoptosis of oral squamous carcinoma tumor cells. Furthermore, PKM2 knockdown could regulate the expression of cell cycle and apoptosis‑related proteins by activating Hippo signaling pathway, as confirmed by the decreased expression of yes‑associated protein 1 (YAP), Bcl‑2 and Ki‑67 and the increased expression of large tumor suppressor kinase 1, phosphorylated YAP and Bax. Taken together, the findings from this study demonstrated that PKM2 may be considered as a potential target for the diagnosis and treatment of OTSCC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar
2	Chi AC, Day TA and Neville BW: Oral cavity and oropharyngeal squamous cell carcinoma-an update. Cancer J Clin. 65:401–421. 2015. View Article : Google Scholar
3	Gillison ML, Chaturvedi AK, Anderson WF and Fakhry C: Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol. 33:32–37. 2015. View Article : Google Scholar
4	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar
5	Tamada M, Suematsu M and Saya H: Pyruvate kinase M2: Multiple faces for conferring benefits on cancer cells. Clin Cancer Res. 18:5554–5561. 2012. View Article : Google Scholar : PubMed/NCBI
6	Luo W and Semenza GL: Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab. 23:560–566. 2012. View Article : Google Scholar : PubMed/NCBI
7	Dayton TL, Jacks T and Vander Heiden MG: PKM2, cancer metabolism, and the road ahead. EMBO Rep. 17:1721–1730. 2016. View Article : Google Scholar : PubMed/NCBI
8	Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL and Cantley LC: The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 452:230–233. 2008. View Article : Google Scholar : PubMed/NCBI
9	Burns JS and Manda G: Metabolic pathways of the Warburg effect in health and disease: Perspectives of choice, chain or chance. Int J Mol Sci. 18:27552017. View Article : Google Scholar : PubMed/NCBI
10	Zhou ZF, Li M, Zhang L, Zhao H, Şahin Ö, Chen J, Zhao JJ, Songyang Z and Yu D: Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts nononcogenic PKM2 to a tumor promoter and induces cancer stem-like cells. Cancer Res. 78:2248–2261. 2018. View Article : Google Scholar : PubMed/NCBI
11	Liu FB, Ma FF, Wang YY, Hao L, Zeng H, Jia C, Wang Y, Liu P, Ong IM, Li B, et al: PKM2 methylation by CARM1 activates aerobic glycolysis to promote tumorigenesis. Nat Cell Biol. 19:1358–1370. 2017. View Article : Google Scholar : PubMed/NCBI
12	Li M, Bai YT, Han K, Li XD and Meng J: Knockdown of ectodysplasin-A receptor-associated adaptor protein exerts a tumor-suppressive effect in tongue squamous cell carcinoma cells. Exp Ther Med. 19:3337–3347. 2020.PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Wu H, Zhang W, Wu Z, Liu Y, Shi Y, Gong J, Shen W and Liu C: miR-29c-3p regulates DNMT3B and LATS1 methylation to inhibit tumor progression in hepatocellular carcinoma. Cell Death Dis. 10:482019. View Article : Google Scholar : PubMed/NCBI
15	Estilo CL, O-charoenrat P, Talbot S, Socci ND, Carlson DL, Ghossein R, Williams T, Yonekawa Y, Ramanathan Y, Boyle JO, et al: Oral tongue cancer gene expression profiling: Identification of novel potential prognosticators by oligonucleotide microarray analysis. BMC Cancer. 9:112009. View Article : Google Scholar : PubMed/NCBI
16	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI
17	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar
18	Solomon B, Young RJ and Rischin D: Head and neck squamous cell carcinoma: Genomics and emerging biomarkers for immunomodulatory cancer treatments. Semin Cancer Biol. 52:228–240. 2018. View Article : Google Scholar : PubMed/NCBI
19	Omura K: Current status of oral cancer treatment strategies: Surgical treatments for oral squamous cell carcinoma. Int J Clin Oncol. 19:423–430. 2014. View Article : Google Scholar : PubMed/NCBI
20	Ali J, Sabiha B, Jan HU, Haider SA, Khan AA and Ali SS: Genetic etiology of oral cancer. Oral Oncol. 70:23–28. 2017. View Article : Google Scholar : PubMed/NCBI
21	Hussein AA, Forouzanfar T, Bloemena E, de Visscher J, Brakenhoff RH, Leemans CR and Helder MN: A review of the most promising biomarkers for early diagnosis and prognosis prediction of tongue squamous cell carcinoma. Br J Cancer. 119:724–736. 2018. View Article : Google Scholar : PubMed/NCBI
22	Kim YJ and Kim JH: Increasing incidence and improving survival of oral tongue squamous cell carcinoma. Sci Rep. 10:78772020. View Article : Google Scholar : PubMed/NCBI
23	Lu J: The Warburg metabolism fuels tumor metastasis. Cancer Metastasis Rev. 38:157–164. 2019. View Article : Google Scholar : PubMed/NCBI
24	Icard P, Shulman S, Farhat D, Steyaert JM, Alifano M and Lincet H: How the Warburg effect supports aggressiveness and drug resistance of cancer cells? Drug Resist Updat. 38:1–11. 2018. View Article : Google Scholar : PubMed/NCBI
25	Wilde L, Roche M, Domingo-Vidal M, Tanson K, Philp N, Curry J and Martinez-Outschoorn U: Metabolic coupling and the reverse Warburg effect in cancer: Implications for novel biomarker and anticancer agent development. Semin Oncol. 44:198–203. 2017. View Article : Google Scholar : PubMed/NCBI
26	Liberti MV and Locasale JW: The Warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 41:211–218. 2016. View Article : Google Scholar : PubMed/NCBI
27	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg Effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
28	Sun L, Suo C, Li ST, Zhang H and Gao P: Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect. Biochim Biophys Acta Rev Cancer. 1870:51–66. 2018. View Article : Google Scholar : PubMed/NCBI
29	Wiese EK and Hitosugi T: Tyrosine kinase signaling in cancer metabolism: PKM2 paradox in the Warburg effect. Front Cell Dev Bio. 6:792018. View Article : Google Scholar
30	van Niekerk G and Engelbrecht AM: Role of PKM2 in directing the metabolic fate of glucose in cancer: A potential therapeutic target. Cell Oncol (Dordr). 41:343–351. 2018. View Article : Google Scholar : PubMed/NCBI
31	Zhang Z, Deng X, Liu Y, Liu Y, Sun L and Chen F: PKM2, function and expression and regulation. Cell Biosci. 9:522019. View Article : Google Scholar : PubMed/NCBI
32	Yang W, Zheng Y and Xia Y: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 14:1295–1304. 2012. View Article : Google Scholar : PubMed/NCBI
33	Li T, Han J, Jia L, Hu X, Chen L and Wang Y: PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation. Protein Cell. 10:583–594. 2019. View Article : Google Scholar : PubMed/NCBI
34	Miao Y, Lu M, Yan Q, Li SD and Feng YJ: Inhibition of proliferation, migration, and invasion by knockdown of pyruvate Kinase-M2 (PKM2) in ovarian cancer SKOV3 and OVCAR3 Cells. Oncol Res. 24:463–475. 2016. View Article : Google Scholar : PubMed/NCBI
35	Liang J, Cao R, Wang X, Zhang Y, Wang P, Gao H, Li C, Yang F, Zeng R, Wei P, et al: Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res. 27:329–351. 2017. View Article : Google Scholar : PubMed/NCBI
36	Xu Q, Tu J, Dou C, Zhang J, Yang L, Liu X, Lei K, Liu Z, Wang Y, Li L, et al: HSP90 promotes cell glycolysis, proliferation and inhibits apoptosis by regulating PKM2 abundance via Thr-328 phosphorylation in hepatocellular carcinoma. Mol Cancer. 16:1782017. View Article : Google Scholar : PubMed/NCBI
37	Wang W, He Q, Sun J, Liu Z, Zhao L, Lu Z, Zhou X and Wang A: Pyruvate kinase M2 deregulation enhances the metastatic potential of tongue squamous cell carcinoma. Oncotarget. 8:68252–68262. 2017. View Article : Google Scholar : PubMed/NCBI
38	Jing C, Qu X, Li Z, Wu C, Zhao M, Wang Y, Sun S, Zhang S, Chen J, Qiao Y, et al: EGFRwt/vIII-PKM2-β-catenin cascade affects proliferation and chemo-sensitivity in head and neck squamous cell carcinoma. Am J Cancer Res. 7:2491–2502. 2017.PubMed/NCBI
39	Kurihara-Shimomura M, Sasahira T, Nakashima C, Kuniyasu H, Shimomura H and Kirita T: The Multifarious functions of pyruvate kinase M2 in oral cancer cells. Int J Mol Sci. 19:29072018. View Article : Google Scholar : PubMed/NCBI