Cytoprotective effect of neuropeptides on cancer stem cells

vasoactive intestinal peptide-induced antiapoptotic signaling

Seetharama S. Konduru, Aouatef Ismail EP Chouchane, Ena Wang, George Kulik, Francesco M. Marincola, Lotfi Chouchane

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Cancer stem cells (CSCs) are increasingly considered to be responsible for tumor initiation, metastasis and drug resistance. The drug resistance mechanisms activated in CSCs have not been thoroughly investigated. Although neuropeptides such as vasoactive intestinal peptide (VIP) can promote tumor growth and activate antiapoptotic signaling in differentiated cancer cells, it is not known whether they can activate antiapoptotic mechanisms in CSCs. The objectives of this study are to unravel the cytoprotective effects of neuropeptides and identify antiapoptotic mechanisms activated by neuropeptides in response to anticancer drug treatment in CSCs. We enriched and purified CSCs (CD44+/high/CD24-/low or CD133+ population) from breast and prostate cancer cell lines, and demonstrated their stemness phenotype. Of the several neuropeptides tested, only VIP could protect CSCs from drug-induced apoptosis. A functional correlation was found between drug-induced apoptosis and dephosphorylation of proapoptotic Bcl2 family protein BAD. Similarly, VIP-induced cytoprotection correlated with BAD phosphorylation at Ser112 in CSCs. Using pharmacological inhibitors and dominant-negative proteins, we showed that VIP-induced cytoprotection and BAD phosphorylation are mediated via both Ras/MAPK and PKA pathways in CSCs of prostate cancer LNCaP and C4-2 cells, but only PKA signaling was involved in CSCs of DUVIPR (DU145 prostate cancer cells ectopically expressing VIP receptor) and breast cancer MCF7 cells. As each of these pathways partially control BAD phosphorylation at Ser112, both have to be inhibited to block the cytoprotective effects of VIP. Furthermore, VIP is unable to protect CSCs that express phosphorylation-deficient mutant-BAD, suggesting that BAD phosphorylation is essential. Thus, antiapoptotic signaling by VIP could be one of the drug resistance mechanisms by which CSCs escape from anticancer therapies. Our findings suggest the potential usefulness of VIP receptor inhibition to eliminate CSCs, and that targeting BAD might be an attractive strategy for development of novel therapeutics.

Original languageEnglish
Pages (from-to)e2844
JournalCell death & disease
Volume8
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017

Fingerprint

Neoplastic Stem Cells
Vasoactive Intestinal Peptide
Neuropeptides
Phosphorylation
Drug Resistance
Vasoactive Intestinal Peptide Receptors
Prostatic Neoplasms
Cytoprotection
Pharmaceutical Preparations
Apoptosis
Breast Neoplasms
Neoplasms
MCF-7 Cells
Proteins
Pharmacology

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Cytoprotective effect of neuropeptides on cancer stem cells : vasoactive intestinal peptide-induced antiapoptotic signaling. / Konduru, Seetharama S.; Ismail EP Chouchane, Aouatef; Wang, Ena; Kulik, George; Marincola, Francesco M.; Chouchane, Lotfi.

In: Cell death & disease, Vol. 8, No. 6, 01.06.2017, p. e2844.

Research output: Contribution to journalArticle

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