Skip to main content

Advertisement

SpringerLink
Log in

LHPP exerts a tumor-inhibiting role in glioblastoma via the downregulation of Akt and Wnt/β-catenin signaling

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been recently identified as a novel inhibitor of multiple tumors; however, its role in glioblastoma (GBM) has not been investigated. This study aimed to evaluate whether LHPP exerts a potential tumor-inhibiting role in GBM. Compared with that in normal tissues, LHPP expression was lower in GBM tissues and various GBM cell lines. LHPP up-regulation in GBM cells markedly reduced their proliferation and invasion, and its knockdown had an oncogenic effect on these cells. Further studies revealed that overexpressed LHPP decreased the levels of Akt and glycogen synthase-3β phosphorylation and down-regulated Wnt/β-catenin signaling. By contrast, LHPP knockdown produced opposite effects. Akt suppression markedly abrogated the activation of Wnt/β-catenin signaling induced by LHPP knockdown. The reactivation of Wnt/β-catenin signaling partially reversed the inhibition of tumor growth in GBM mediated by LHPP overexpression. In addition, LHPP overexpression markedly retarded the tumorigenesis of GBM cells in vivo. These findings revealed that LHPP acts a potential inhibitor of tumor growth in GBM, and its overexpression represses GBM proliferation and invasion by down-regulating Akt and Wnt/β-catenin signaling. This work highlights the crucial role of LHPP in GBM progression and suggests its potential as an anticancer target for the treatment of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

Data availability

Data and material used to support the findings of this study are available from the corresponding author upon request.

References

  • Atkins RJ, Stylli SS, Luwor RB, Kaye AH, Hovens CM (2013) Glycogen synthase kinase-3β (GSK-3β) and its dysregulation in glioblastoma multiforme. J Clin Neurosci 20:1185–1192

    Article  CAS  Google Scholar 

  • Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W (1998) Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science 280:596–599

    Article  CAS  Google Scholar 

  • Boele FW, Given CW, Given BA, Donovan HS, Schulz R, Weimer JM, Drappatz J, Lieberman FS, Sherwood PR (2017) Family caregivers' level of mastery predicts survival of patients with glioblastoma: a preliminary report. Cancer 123:832–840

    Article  CAS  Google Scholar 

  • Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205

    Article  CAS  Google Scholar 

  • Cui L, Gong X, Tang Y, Kong L, Chang M, Geng H, Xu K, Wang F (2016) Relationship between the LHPP gene polymorphism and resting-state brain activity in major depressive disorder. Neural Plast 2016:9162590

    Article  Google Scholar 

  • Guo Y, Jia P, Chen Y, Yu H, Xin X, Bao Y, Yang H, Wu N, Sun Y, Jia D (2020) PHLDA1 is a new therapeutic target of oxidative stress and ischemia reperfusion-induced myocardial injury. Life Sci 245:117347

    Article  CAS  Google Scholar 

  • Gutierrez-Camino A, Martin-Guerrero I, García-Orad A (2017) Genetic susceptibility in childhood acute lymphoblastic leukemia. Med Oncol 34:179

    Article  Google Scholar 

  • Hindupur SK, Colombi M, Fuhs SR, Matter MS, Guri Y, Adam K, Cornu M, Piscuoglio S, Ng CKY, Betz C, Liko D, Quagliata L, Moes S, Jenoe P, Terracciano LM, Heim MH, Hunter T, Hall MN (2018) The protein histidine phosphatase LHPP is a tumour suppressor. Nature 555:678–682

    Article  CAS  Google Scholar 

  • Hong T, Li R, Sun LL, Xu J, He MT, Wang W, Yan R, Tong J, Zhang J (2019) Role of the gene Phlda1 in fenvalerate-induced apoptosis and testicular damage in Sprague-Dawley rats. J Toxicol Environ Health A 82:870–878

    Article  CAS  Google Scholar 

  • Hou B, Li W, Li J, Ma J, Xia P, Liu Z, Zeng Q, Zhang X, Chang D (2020) Tumor suppressor LHPP regulates the proliferation of colorectal cancer cells via the PI3K/AKT pathway. Oncol Rep 43:536–548

    CAS  PubMed  Google Scholar 

  • Hu HH, Cao G, Wu XQ, Vaziri ND, Zhao YY (2020) Wnt signaling pathway in aging-related tissue fibrosis and therapies. Ageing Res Rev 60:101063

    Article  CAS  Google Scholar 

  • Hussain M, Xu C, Lu M, Wu X, Tang L, Wu X (2017) Wnt/β-catenin signaling links embryonic lung development and asthmatic airway remodeling. Biochim Biophys Acta Mol basis Dis 1863:3226–3242

    Article  CAS  Google Scholar 

  • Knowles EE, Kent JW Jr, McKay DR, Sprooten E, Mathias SR, Curran JE, Carless MA, de Almeida MA, Harald HH, Dyer TD, Olvera RL, Fox PT, Duggirala R, Almasy L, Blangero J, Glahn DC (2016) Genome-wide linkage on chromosome 10q26 for a dimensional scale of major depression. J Affect Disord 191:123–131

    Article  CAS  Google Scholar 

  • Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, Lacko M, Eluf-Neto J, Franceschi S, Lagiou P, Macfarlane GJ, Richiardi L, Boccia S, Polesel J, Kjaerheim K, Zaridze D, Johansson M, Menezes AM, Curado MP, Robinson M, Ahrens W, Canova C, Znaor A, Castellsagué X, Conway DI, Holcátová I, Mates D, Vilensky M, Healy CM, Szeszenia-Dąbrowska N, Fabiánová E, Lissowska J, Grandis JR, Weissler MC, Tajara EH, Nunes FD, de Carvalho MB, Thomas S, Hung RJ, Peters WH, Herrero R, Cadoni G, Bueno-de-Mesquita HB, Steffen A, Agudo A, Shangina O, Xiao X, Gaborieau V, Chabrier A, Anantharaman D, Boffetta P, Amos CI, McKay JD, Brennan P (2016) Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet 48:1544–1550

    Article  CAS  Google Scholar 

  • Li Y, Zhang X, Zhou X, Zhang X (2019) LHPP suppresses bladder cancer cell proliferation and growth via inactivating AKT/p65 signaling pathway. Biosci Rep 39:BSR20182270

    Article  Google Scholar 

  • McCord M, Mukouyama YS, Gilbert MR, Jackson S (2017) Targeting WNT signaling for multifaceted glioblastoma therapy. Front Cell Neurosci 11:318

    Article  Google Scholar 

  • Neff CD, Abkevich V, Packer JC, Chen Y, Potter J, Riley R, Davenport C, DeGrado WJ, Jammulapati S, Bhathena A, Choi WS, Kroeger PE, Metzger RE, Gutin A, Skolnick MH, Shattuck D, Katz DA (2009) Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Mol Psychiatry 14:621–630

    Article  CAS  Google Scholar 

  • Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850

    Article  CAS  Google Scholar 

  • Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro-Oncology 21:v1–v100

    Article  Google Scholar 

  • Polimanti R, Wang Q, Meda SA, Patel KT, Pearlson GD, Zhao H, Farrer LA, Kranzler HR, Gelernter J (2017) The interplay between risky sexual behaviors and alcohol dependence: genome-wide association and neuroimaging support for LHPP as a risk gene. Neuropsychopharmacology 42:598–605

    Article  CAS  Google Scholar 

  • Stamos JL, Weis WI (2013) The beta-catenin destruction complex. Cold Spring Harb Perspect Biol 5:a007898

    Article  Google Scholar 

  • Sun W, Qian K, Guo K, Chen L, Xiang J, Li D, Wu Y, Ji Q, Sun T, Wang Z (2020) LHPP inhibits cell growth and migration and triggers autophagy in papillary thyroid cancer by regulating the AKT/AMPK/mTOR signaling pathway. Acta Biochim Biophys Sin Shanghai 52:382–389

    Article  CAS  Google Scholar 

  • Tompa M, Kalovits F, Nagy A, Kalman B (2018) Contribution of the Wnt pathway to defining biology of glioblastoma. NeuroMolecular Med 20:437–451

    Article  CAS  Google Scholar 

  • Velásquez C, Mansouri S, Mora C, Nassiri F, Suppiah S, Martino J, Zadeh G, Fernández-Luna JL (2019) Molecular and clinical insights into the invasive capacity of Glioblastoma cells. J Oncol 2019:1740763

    Article  Google Scholar 

  • Vijayakrishnan J, Kumar R, Henrion MY, Moorman AV, Rachakonda PS, Hosen I, da Silva Filho MI, Holroyd A, Dobbins SE, Koehler R, Thomsen H, Irving JA, Allan JM, Lightfoot T, Roman E, Kinsey SE, Sheridan E, Thompson PD, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Jöckel KH, Greaves M, Harrison CJ, Bartram CR, Schrappe M, Stanulla M, Hemminki K, Houlston RS (2017) A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1. Leukemia 31:573–579

    Article  CAS  Google Scholar 

  • Wu F, Chen Y, Zhu J (2020) LHPP suppresses proliferation, migration, and invasion and promotes apoptosis in pancreatic cancer. Biosci Rep 40:BSR20194142

    Article  CAS  Google Scholar 

  • Yan J, He L, Li G, Peng X, Li W, Liu X, Yang D, Liu J, Zhang P, Lu X (2020) Clinical value of serum LHPP-associated miR-765 in the prognosis of laparoscopic or open hepatectomy for hepatocellular carcinoma. Surg Laparosc Endosc Percutan Tech 5:12

    Article  Google Scholar 

  • Yokoi F, Hiraishi H, Izuhara K (2003) Molecular cloning of a cDNA for the human phospholysine phosphohistidine inorganic pyrophosphate phosphatase. J Biochem 133:607–614

    Article  CAS  Google Scholar 

  • Zhang Q, Xiong M, Liu J, Wang S, Du T, Kang T, Liu Y, Cheng H, Huang M, Gou M (2019) Targeted nanoparticle-mediated LHPP for melanoma treatment. Int J Nanomedicine 14:3455–3468

    Article  CAS  Google Scholar 

  • Zheng J, Dai X, Chen H, Fang C, Chen J, Sun L (2018) Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT. Biochem Biophys Res Commun 503:1108–1114

    Article  CAS  Google Scholar 

  • Zhong Z, Yu J, Virshup DM, Madan B (2020) Wnts and the hallmarks of cancer. Cancer Metastasis Rev 5:6

    Google Scholar 

Download references

Funding

This study was supported by the Natural Science Foundation Research Project of Shaanxi Province (2020JQ-509).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

    Chuankun Li, Wei Wang & Ruichun Li

  2. The Department of Operation, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Jingya Yang

Authors
  1. Chuankun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingya Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruichun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chuankun Li designed the study, performed experiments, and drafted the manuscript. Jingya Yang performed experiments. Wei Wang analyzed and interpreted the data. Ruichun Li analyzed and interpreted the data.

Corresponding author

Correspondence to Chuankun Li.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethics approval

Human samples were used with the approval of the Ethics Committee of Xi’an Jiaotong University, and experiments were conducted in compliance with the regulations of Helsinki Declaration. Animal experiments were approved by the Ethics Committee of Xi’an Jiaotong University.

Consent to participate

Written informed consent regarding tissue donation for experimental research was acquired from each participant.

Consent for publication

All authors have approved the publication of this manuscript.

Code availability

Not applicable

Additional information

Publisher’s note

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

Supplementary Information

ESM 1

(DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Yang, J., Wang, W. et al. LHPP exerts a tumor-inhibiting role in glioblastoma via the downregulation of Akt and Wnt/β-catenin signaling. J Bioenerg Biomembr 53, 61–71 (2021). https://doi.org/10.1007/s10863-020-09866-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-020-09866-0

Keywords

Search

Navigation