PKM2 promotes cell metastasis and inhibits autophagy via the JAK/STAT3 pathway in hepatocellular carcinoma

Abstract

Pyruvate kinase M2 (PKM2) is a member of the pyruvate kinase family. It has been recently reported that PKM2 displays non-metabolic activities. Nevertheless, understanding of the role of PKM2 in hepatocellular carcinoma (HCC) is insufficient. Therefore, our study aimed at exploring the impact of PKM2 on malignant growth, autophagy as well as invasion in HCC. Expression of PKM2 in HCC specimens was examined by qRT-PCR and western blot. PKM2 knock down was generated in vitro by shRNA. Activities of malignant cells as well as downstream pathways were assessed. The MTT assay was carried out to evaluate HCC proliferation, and the FACS assay was conducted to study cell death. Elevated PKM2 levels were observed in HCC samples. Knockdown (KD) of PKM2 triggered apoptosis as well as autophagy and inhibited migration and proliferation of HCC cells. Furthermore, PKM2 KD reinforced JAK/STAT3 pathway stimulation. STAT3 inhibition counteracted the impact of PKM2 on proliferation, autophagy, migration as well as cell death in HCC. To conclude, the findings of our research suggest that PKM2 reinforced metastasis and inhibited autophagy in HCC through the JAK/STAT3 pathway, and that PKM2 could serve as a promising target for HCC treatment.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Data availability

My manuscript has no associated data.

References

  1. 1.

    Schwarz C, Fitschek F, Mittlbock M, Saukel V, Bota S, Ferlitsch M, Ferlitsch A, Bodingbauer M, Kaczirek K (2020) von Willebrand factor antigen predicts outcomes in patients after liver resection of hepatocellular carcinoma. Gut Liver 14:218–224. https://doi.org/10.5009/gnl17115

    Article  PubMed  Google Scholar 

  2. 2.

    Tseng PL, Wu WH, Hu TH, Chen CW, Cheng HC, Li CF, Tsai WH, Tsai HJ, Hsieh MC, Chuang JH, Chang WT (2018) Decreased succinate dehydrogenase B in human hepatocellular carcinoma accelerates tumor malignancy by inducing the Warburg effect. Sci Rep 8:3081. https://doi.org/10.1038/s41598-018-21361-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Liu W, Kang L, Han J, Wang Y, Shen C, Yan Z, Tai Y, Zhao C (2018) miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect. Onco Targets Ther 11:1643–1653. https://doi.org/10.2147/OTT.S161586

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Zarrinpar A, Faltermeier CM, Agopian VG, Naini BV, Harlander-Locke MP, Kaldas FM, Farmer DG, Busuttil RW (2019) Metabolic factors affecting hepatocellular carcinoma in steatohepatitis. Liver Int 39:531–539. https://doi.org/10.1111/liv.14002

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Zhao B, Fan S, Fan Z, Wang H, Zhang N, Guo X, Yang D, Wu Q, Yu B, Zhou S (2018) Discovery of pyruvate kinase as a novel target of new fungicide candidate 3-(4-methyl-1,2,3-thiadiazolyl)-6-trichloromethyl-[1,2,4]-triazolo-[3,4- b][1,3,4]-thiadizole. J Agric Food Chem 66:12439–12452. https://doi.org/10.1021/acs.jafc.8b03797

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Miao G, Han J, Zhang J, Wu Y, Tong G (2019) Targeting pyruvate kinase M2 and hexokinase II, pachymic acid impairs glucose metabolism and induces mitochondrial apoptosis. Biol Pharm Bull 42:123–129. https://doi.org/10.1248/bpb.b18-00730

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Yao A, Xiang Y, Si YR, Fan LJ, Li JP, Li H, Guo W, He HX, Liang XJ, Tan Y, Bao LY, Liao XH (2019) PKM2 promotes glucose metabolism through a let-7a-5p/Stat3/hnRNP-A1 regulatory feedback loop in breast cancer cells. J Cell Biochem 120:6542–6554. https://doi.org/10.1002/jcb.27947

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Gao S, Chen M, Wei W, Zhang X, Zhang M, Yao Y, Lv Y, Ling T, Wang L, Zou X (2018) Crosstalk of mTOR/PKM2 and STAT3/c-Myc signaling pathways regulate the energy metabolism and acidic microenvironment of gastric cancer. J Cell Biochem. https://doi.org/10.1002/jcb.26915

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Lin Y, Meng F, Lu Z, Chen K, Tao Y, Ouyang Y, Cao X (2018) Knockdown of PKM2 suppresses tumor progression in human cervical cancer by modulating epithelial-mesenchymal transition via Wnt/beta-catenin signaling. Cancer Manag Res 10:4191–4202. https://doi.org/10.2147/CMAR.S178219

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kurihara-Shimomura M, Sasahira T, Nakashima C, Kuniyasu H, Shimomura H, Kirita T (2018) The multifarious functions of pyruvate kinase M2 in oral cancer cells. Int J Mol Sci 19:2907. https://doi.org/10.3390/ijms19102907

    CAS  Article  PubMed Central  Google Scholar 

  11. 11.

    Wiese EK, Hitosugi T (2018) Tyrosine kinase signaling in cancer metabolism: PKM2 paradox in the Warburg effect. Front Cell Dev Biol 6:79. https://doi.org/10.3389/fcell.2018.00079

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ma T, Patel H, Babapoor-Farrokhran S, Franklin R, Semenza GL, Sodhi A, Montaner S (2015) KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi’s sarcoma. Angiogenesis 18:477–488. https://doi.org/10.1007/s10456-015-9475-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Johnson DE, O’Keefe RA, Grandis JR (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234–248. https://doi.org/10.1038/nrclinonc.2018.8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Sakamoto A, Kunou S, Shimada K, Tsunoda M, Aoki T, Iriyama C, Tomita A, Nakamura S, Hayakawa F, Kiyoi H (2019) Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells. Cancer Sci 110:269–278. https://doi.org/10.1111/cas.13873

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Zhu Q, Hong B, Zhang L, Wang J (2018) Pyruvate kinase M2 inhibits the progression of bladder cancer by targeting MAKP pathway. J Cancer Res Ther 14:S616–S621. https://doi.org/10.4103/0973-1482.187302

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Yang Y, Meng Q, Wang C, Li X, Lu Y, Xin X, Zheng Q, Lu D (2018) MicroRNA 675 cooperates PKM2 to aggravate progression of human liver cancer stem cells induced from embryonic stem cells. J Mol Med 96:1119–1130. https://doi.org/10.1007/s00109-018-1687-9

    Article  PubMed  Google Scholar 

  17. 17.

    Hasan D, Gamen E, Abu Tarboush N, Ismail Y, Pak O, Azab B (2018) PKM2 and HIF-1alpha regulation in prostate cancer cell lines. PLoS ONE 13:e0203745. https://doi.org/10.1371/journal.pone.0203745

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Cao Y, Lin Y, Wang D, Pan D, Zhang Y, Jin Y, Zheng C (2018) Enhancing 5-fluorouracil efficacy through suppression of PKM2 in colorectal cancer cells. Cancer Chemother Pharmacol 82:1081–1086. https://doi.org/10.1007/s00280-018-3676-7

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Yasumizu Y, Hongo H, Kosaka T, Mikami S, Nishimoto K, Kikuchi E, Oya M (2018) PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer. Oncotarget 9:27698–27707. https://doi.org/10.18632/oncotarget.25498

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    van Niekerk G, Engelbrecht AM (2018) Role of PKM2 in directing the metabolic fate of glucose in cancer: a potential therapeutic target. Cell Oncol (Dordr) 41:343–351. https://doi.org/10.1007/s13402-018-0383-7

    CAS  Article  Google Scholar 

  21. 21.

    Li Q, Cao L, Tian Y, Zhang P, Ding C, Lu W, Jia C, Shao C, Liu W, Wang D, Ye H, Hao H (2018) Butyrate suppresses the proliferation of colorectal cancer cells via targeting pyruvate kinase M2 and metabolic reprogramming. Mol Cell Proteom 17:1531–1545. https://doi.org/10.1074/mcp.RA118.000752

    CAS  Article  Google Scholar 

  22. 22.

    Qian Y, Bi L, Yang Y, Wang D (2018) Effect of pyruvate kinase M2-regulating aerobic glycolysis on chemotherapy resistance of estrogen receptor-positive breast cancer. Anticancer Drugs 29:616–627. https://doi.org/10.1097/CAD.0000000000000624

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Zheng B, Liu F, Zeng L, Geng L, Ouyang X, Wang K, Huang Q (2018) Overexpression of pyruvate kinase type M2 (PKM2) promotes ovarian cancer cell growth and survival via regulation of cell cycle progression related with upregulated CCND1 and downregulated CDKN1A expression. Med Sci Monit 24:3103–3112. https://doi.org/10.12659/MSM.907490

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bian Z, Zhang J, Li M, Feng Y, Wang X, Zhang J, Yao S, Jin G, Du J, Han W, Yin Y, Huang S, Fei B, Zou J, Huang Z (2018) LncRNA-FEZF1-AS1 promotes tumor proliferation and metastasis in colorectal cancer by regulating PKM2 signaling. Clin Cancer Res 24:4808–4819. https://doi.org/10.1158/1078-0432.CCR-17-2967

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Liu BW, Wang TJ, Li LL, Zhang L, Liu YX, Feng JY, Wu Y, Xu FF, Zhang QS, Bao MZ, Zhang WY, Ye LH (2019) Oncoprotein HBXIP induces PKM2 via transcription factor E2F1 to promote cell proliferation in ER-positive breast cancer. Acta Pharmacol Sin 40:530–538. https://doi.org/10.1038/s41401-018-0015-9

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Li RZ, Fan XX, Shi DF, Zhu GY, Wang YW, Luo LX, Pan HD, Yao XJ, Leung EL, Liu L (2018) Identification of a new pyruvate kinase M2 isoform (PKM2) activator for the treatment of non-small-cell lung cancer (NSCLC). Chem Biol Drug Des 92:1851–1858. https://doi.org/10.1111/cbdd.13354

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Zhang K, Zhang M, Jiang H, Liu F, Liu H, Li Y (2018) Down-regulation of miR-214 inhibits proliferation and glycolysis in non-small-cell lung cancer cells via down-regulating the expression of hexokinase 2 and pyruvate kinase isozyme M2. Biomed Pharmacother 105:545–552. https://doi.org/10.1016/j.biopha.2018.06.009

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Grander D, Panaretakis T (2010) Autophagy: cancer therapy’s friend or foe? Future Med Chem 2:285–297. https://doi.org/10.4155/fmc.09.155

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Pavlides S, Vera I, Gandara R, Sneddon S, Pestell RG, Mercier I, Martinez-Outschoorn UE, Whitaker-Menezes D, Howell A, Sotgia F, Lisanti MP (2012) Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal 16:1264–1284. https://doi.org/10.1089/ars.2011.4243

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Livesey KM, Tang D, Zeh HJ, Lotze MT (2008) Not just nuclear proteins: “novel” autophagy cancer treatment targets: p53 and HMGB1. Curr Opin Investig Drugs 9:1259–1263

    PubMed  Google Scholar 

  31. 31.

    Zhang B, Yin X, Sui S (2018) Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide 3kinase/protein kinase B pathway. Oncol Rep 40:2758–2765. https://doi.org/10.3892/or.2018.6648

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Chang R, Song L, Xu Y, Wu Y, Dai C, Wang X, Sun X, Hou Y, Li W, Zhan X, Zhan L (2018) Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nat Commun 9:3486. https://doi.org/10.1038/s41467-018-05852-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ma J, Song X, Xu X, Mou Y (2019) Cancer-associated fibroblasts promote the chemo-resistance in gastric cancer through secreting IL-11 targeting JAK/STAT3/Bcl2 pathway. Cancer Res Treat 51:194–210. https://doi.org/10.4143/crt.2018.031

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Xue J, Liao L, Yin F, Kuang H, Zhou X, Wang Y (2018) LncRNA AB073614 induces epithelial-mesenchymal transition of colorectal cancer cells via regulating the JAK/STAT3 pathway. Cancer Biomark 21:849–858. https://doi.org/10.3233/CBM-170780

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Li M, Zheng R, Yuan FL (2018) MiR-410 affects the proliferation and apoptosis of lung cancer A549 cells through regulation of SOCS3/JAK-STAT signaling pathway. Eur Rev Med Pharmacol Sci 22:5987–5993. https://doi.org/10.26355/eurrev_201809_15933

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yingying Tang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yu, Z., Wang, D. & Tang, Y. PKM2 promotes cell metastasis and inhibits autophagy via the JAK/STAT3 pathway in hepatocellular carcinoma. Mol Cell Biochem (2021). https://doi.org/10.1007/s11010-020-04041-w

Download citation

Keywords

  • Apoptosis
  • Autophagy
  • Hepatocellular carcinoma
  • JAK/STAT3
  • PKM2