International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

Parathyroid Hormone-Related Protein Promotes the Proliferation of Patient-Derived Glioblastoma Stem Cells via Activating cAMP/PKA Signaling Pathway

  • Zhenyu Guo (Department of Neurosurgery, The 2nd Affiliated Hospital of Xi'an Jiaotong University) ;
  • Tingqin Huang (Department of Neurosurgery, The 2nd Affiliated Hospital of Xi'an Jiaotong University) ;
  • Yingfei Liu (Institute of Neurobiology, Xi'an Jiaotong University Health Science Center) ;
  • Chongxiao Liu (Department of Neurosurgery, The 2nd Affiliated Hospital of Xi'an Jiaotong University)
  • Received : 2022.06.11
  • Accepted : 2022.11.01
  • Published : 2023.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

Keywords

Acknowledgement

We thank Dr. Zhichao Zhang for his technical assistance.

References

  1. Ahir BK, Engelhard HH, Lakka SS. Tumor development and angiogenesis in adult brain tumor: glioblastoma. Mol Neurobiol 2020;57:2461-2478 
  2. Zhang Z, Zheng X, Luan Y, Liu Y, Li X, Liu C, Lu H, Chen X, Liu Y. Activity of metabotropic glutamate receptor 4 suppresses proliferation and promotes apoptosis with inhibition of gli-1 in human glioblastoma cells. Front Neurosci 2018;12:320 
  3. Lathia JD, Mack SC, Mulkearns-Hubert EE, Valentim CL, Rich JN. Cancer stem cells in glioblastoma. Genes Dev 2015;29:1203-1217 
  4. Prager BC, Bhargava S, Mahadev V, Hubert CG, Rich JN. Glioblastoma stem cells: driving resilience through chaos. Trends Cancer 2020;6:223-235 
  5. Frieling JS, Lynch CC. Proteolytic regulation of parathyroid hormone-related protein: functional implications for skeletal malignancy. Int J Mol Sci 2019;20:2814 
  6. Lai NK, Martinez D. Physiological roles of parathyroid hormone-related protein. Acta Biomed 2019;90:510-516 
  7. Kim JW, Park N, Kang J, Kim Y, Jung H, Rim YA, Ju JH. Increased potential of bone formation with the intravenous injection of a parathyroid hormone-related protein minicircle DNA vector. Int J Mol Sci 2021;22:9069 
  8. Pieles O, Reichert TE, Morsczeck C. Protein kinase A is activated during bone morphogenetic protein 2-induced osteogenic differentiation of dental follicle stem cells via endogenous parathyroid hormone-related protein. Arch Oral Biol 2022;138:105409 
  9. Liu Y, Wang Q, Wang Q, Cui M, Jin Y, Wang R, Mao Z, Miao D, Karaplis AC, Zhang YP, Shields LBE, Shields CB, Zhang Y. Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development. Dev Neurobiol 2021;81:47-62 
  10. Montgrain PR, Deftos LJ, Arenberg D, Tipps A, Quintana R, Carskadon S, Hastings RH. Prognostic implications of parathyroid hormone-related protein in males and females with non--small-cell lung cancer. Clin Lung Cancer 2011;12:197-205 
  11. McCauley LK, Martin TJ. Twenty-five years of PTHrP progress: from cancer hormone to multifunctional cytokine. J Bone Miner Res 2012;27:1231-1239 
  12. Fleming NI, Trivett MK, George J, Slavin JL, Murray WK, Moseley JM, Anderson RL, Thomas DM. Parathyroid hormone-related protein protects against mammary tumor emergence and is associated with monocyte infiltration in ductal carcinoma in situ. Cancer Res 2009;69:7473-7479 Erratum in: Cancer Res 2009;69:8832 
  13. Li J, Karaplis AC, Huang DC, Siegel PM, Camirand A, Yang XF, Muller WJ, Kremer R. PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target. J Clin Invest 2011;121:4655-4669 
  14. Azari H, Millette S, Ansari S, Rahman M, Deleyrolle LP, Reynolds BA. Isolation and expansion of human glioblastoma multiforme tumor cells using the neurosphere assay. J Vis Exp 2011;(56):e3633 
  15. Liu Y, Luan Y, Ma K, Zhang Z, Liu Y, Chen X. ISL1 promotes human glioblastoma-derived stem cells' self-renewal by activation of sonic hedgehog/GLI1 function. Stem Cells Dev 2022;31:258-268 
  16. Zhang Z, Zheng X, Liu Y, Luan Y, Wang L, Zhao L, Zhang J, Tian Y, Lu H, Chen X, Liu Y. Activation of metabotropic glutamate receptor 4 regulates proliferation and neural differentiation in neural stem/progenitor cells of the rat subventricular zone and increases phosphatase and tensin homolog protein expression. J Neurochem 2021;156:465-480 
  17. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Invest 2017;127:415-426 
  18. Liu S, Jean-Alphonse FG, White AD, Wootten D, Sexton PM, Gardella TJ, Vilardaga JP, Gellman SH. Use of backbone modification to enlarge the spatiotemporal diversity of parathyroid hormone receptor-1 signaling via biased agonism. J Am Chem Soc 2019;141:14486-14490 
  19. Nagle PW, Plukker JTM, Muijs CT, van Luijk P, Coppes RP. Patient-derived tumor organoids for prediction of cancer treatment response. Semin Cancer Biol 2018;53:258-264 
  20. Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab 2012;97:2947-2956 
  21. Jin J, Chung JO, Chung MY, Cho DH, Chung DJ. Clinical characteristics, causes and survival in 115 cancer patients with parathyroid hormone related protein-mediated hypercalcemia. J Bone Metab 2017;24:249-255 
  22. Donovan PJ, Achong N, Griffin K, Galligan J, Pretorius CJ, McLeod DS. PTHrP-mediated hypercalcemia: causes and survival in 138 patients. J Clin Endocrinol Metab 2015;100:2024-2029 Erratum in: J Clin Endocrinol Metab 2019;104:2614 
  23. Nakajima T, Konda Y, Kanai M, Izumi Y, Kanda N, Nanakin A, Kitazawa S, Chiba T. Prohormone convertase furin has a role in gastric cancer cell proliferation with parathyroid hormone-related peptide in a reciprocal manner. Dig Dis Sci 2002;47:2729-2737 
  24. Luparello C, Romanotto R, Tipa A, Sirchia R, Olmo N, Lopez de Silanes I, Turnay J, Lizarbe MA, Stewart AF. Midregion parathyroid hormone-related protein inhibits growth and invasion in vitro and tumorigenesis in vivo of human breast cancer cells. J Bone Miner Res 2001;16:2173-2181 
  25. Sassone-Corsi P. The cyclic AMP pathway. Cold Spring Harb Perspect Biol 2012;4:a011148 
  26. Naviglio S, Caraglia M, Abbruzzese A, Chiosi E, Di Gesto D, Marra M, Romano M, Sorrentino A, Sorvillo L, Spina A, Illiano G. Protein kinase A as a biological target in cancer therapy. Expert Opin Ther Targets 2009;13:83-92 
  27. Vert G, Chory J. Crosstalk in cellular signaling: background noise or the real thing? Dev Cell 2011;21:985-991