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Neuregulin promotes incomplete autophagy of prostate cancer cells that is independent of mTOR pathway inhibition.

AbstractBACKGROUND:
Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death.
METHODOLOGY/PRINCIPAL FINDINGS:
In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited.
CONCLUSIONS/SIGNIFICANCE:
Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition.
AuthorsEran Schmukler, Ben Shai, Marcelo Ehrlich, Ronit Pinkas-Kramarski
JournalPloS one (PLoS One) Vol. 7 Issue 5 Pg. e36828 ( 2012) ISSN: 1932-6203 [Electronic] United States
PMID22606295 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anthracenes
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Neuregulins
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Recombinant Proteins
  • pyrazolanthrone
  • 3-methyladenine
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Adenine
  • Acetylcysteine
Topics
  • Acetylcysteine (pharmacology)
  • Adenine (analogs & derivatives, pharmacology)
  • Anthracenes (pharmacology)
  • Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
  • Autophagy (drug effects, physiology)
  • Beclin-1
  • Cell Death (drug effects, physiology)
  • Cell Line, Tumor
  • Humans
  • MAP Kinase Signaling System (drug effects)
  • Male
  • Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
  • Neoplasms, Hormone-Dependent (drug therapy, pathology, physiopathology)
  • Neuregulins (pharmacology, physiology)
  • Prostatic Neoplasms (drug therapy, pathology, physiopathology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Recombinant Proteins (pharmacology)
  • Signal Transduction (drug effects)
  • TOR Serine-Threonine Kinases (antagonists & inhibitors, physiology)

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