Background
The overall survival for neuroblastoma remains dismal, in part due to the emergence
of resistance to chemotherapeutic drugs. We have demonstrated that gastrin-releasing
peptide (GRP), a gut peptide secreted by neuroblastoma, acts as an autocrine growth
factor. We hypothesized that knockdown of GRP will induce apoptosis in neuroblastoma
cells and potentiate the cytotoxic effects of chemotherapeutic agents.
Methods
The human neuroblastoma cell lines (JF, SK-N-SH) were transfected with small interfering
(si) RNA targeted at GRP. Apoptosis was assessed by DNA fragmentation assay. Immunoblotting
was used to confirm molecular markers of apoptosis, and flow cytometry was performed
to determine cell cycle arrest after GRP knockdown.
Results
siGRP resulted in an increase in apoptosis in the absence of chemotherapeutic interventions.
A combination of GRP silencing and chemotherapeutic drugs resulted in enhanced apoptosis
when compared to either of the treatments alone. GRP silencing led to increased expression
of proapoptotic proteins, p53 and p21.
Conclusion
Silencing of GRP induces apoptosis in neuroblastoma cells; it acts synergistically
with chemotherapeutic effects of etoposide and vincristine. GRP knockdown-mediated
apoptosis appears to be associated with upregulation of p53 in neuroblastoma cells.
Targeting GRP may be postulated as a potential novel agent for combinational treatment
to treat aggressive neuroblastomas.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Chemotherapy-induced apoptosis in a transgenic model of neuroblastoma proceeds through p53 induction.Neoplasia. 2008; 10: 1268-1274
- Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells.Mol Cancer. 2009; 8: 80
- Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade.J Biol Chem. 2000; 275: 29980-29985
- Vincristine induced neurotoxicity in cancer patients.Indian J Pediatr. 2010; 77: 97-100
- Etoposide induces protein kinase Cdelta- and caspase-3-dependent apoptosis in neuroblastoma cancer cells.Mol Pharmacol. 2009; 76: 632-640
- Gastrin-releasing peptide and cancer.Biochim Biophys Acta. 2006; 1766: 23-41
- Gastrin-releasing peptide is a growth factor for human neuroblastomas.Ann Surg. 2002; 235: 621-629
- Phosphatidylinositol 3-kinase regulation of gastrin-releasing peptide-induced cell cycle progression in neuroblastoma cells.Biochim Biophys Acta. 2007; 1770: 927-932
- Bombesin antagonists inhibit in vitro and in vivo growth of human gastric cancer and binding of bombesin to its receptors.J Cancer Res Clin Oncol. 1994; 120: 519-528
- Bombesin induces angiogenesis and neuroblastoma growth.Cancer Lett. 2007; 253: 273-281
- Targeting gastrin-releasing peptide receptors on small cell lung cancer cells with a bispecific molecule that activates polyclonal T lymphocytes.Clin Cancer Res. 2006; 12: 2224-2231
- Targeted chemotherapy with cytotoxic bombesin analogue AN-215 inhibits growth of experimental human prostate cancers.Int J Cancer. 2006; 118: 222-229
- Bombesin/gastrin-releasing peptide receptor: a potential target for antibody-mediated therapy of small cell lung cancer.Clin Cancer Res. 2003; 9: 4953-4960
- MYCN silencing induces differentiation and apoptosis in human neuroblastoma cells.Biochem Biophys Res Commun. 2006; 351: 192-197
- The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide.Biochem Pharmacol. 2003; 66: 459-469
- Bombesin stimulation of DNA synthesis and cell division in cultures of Swiss 3T3 cells.Proc Natl Acad Sci U S A. 1983; 80: 2936-2940
- Effects of bombesin on growth of human small cell lung carcinoma in vivo.Cancer Res. 1988; 48: 1439-1441
- Gastrin-releasing peptide-induced down-regulation of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten) in neuroblastomas.Ann Surg. 2005; 241: 684-691
- Inhibition of growth of experimental human and hamster pancreatic cancers in vivo by a targeted cytotoxic bombesin analog.Pancreas. 2005; 31: 275-282
- Alterations of EGFR/HER, angiogenesis and apoptosis pathways after therapy with antagonists of growth hormone releasing hormone and bombesin in non-small cell lung cancer.Int J Oncol. 2007; 30: 1019-1028
- Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer.Mol Cancer Ther. 2007; 6: 1414-1424
- Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo.Surgery. 2009; 146: 282-290
- Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN.Nat Med. 2000; 6: 529-535
- Wild-type p53 can induce p21 and apoptosis in neuroblastoma cells but the DNA damage-induced G1 checkpoint function is attenuated.Clin Cancer Res. 1999; 5: 4199-4207
- Cytoplasmic sequestration of wild-type p53 protein impairs the G1 checkpoint after DNA damage.Mol Cell Biol. 1996; 16: 1126-1137
- P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest.Cancer Res. 2003; 63: 3840-3844
Article info
Publication history
Published online: November 01, 2010
Accepted:
August 10,
2010
Footnotes
Supported by grant R01 DK61479 from the National Institutes of Health.
Identification
Copyright
© 2011 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
