Neuregulin promotes autophagic cell death of prostate cancer cells.
BACKGROUND
Prostate cancer is one of the most frequently diagnosed cancers in males. Autocrine/paracrine growth factors for the epidermal growth factor receptor (EGFR) have been identified in prostate tumors suggesting a role for EGFR in the progression of prostate cancer. The androgen-dependent prostate cancer cell line, LNCaP, expresses the EGFR as well as two additional members of the family; ErbB-2 and ErbB-3, which can be activated by neuregulin (NRG) isoforms. The effect of ErbB ligands on the viability of LNCaP cells was studied.


METHODS
In the present study, we examined the effect of NRG on LNCaP cell growth and survival in the absence of androgen mimetic by the MTT assay, FACS analysis, nuclei staining, and Western blotting.


RESULTS
Our results demonstrate that NRG activates ErbB-2/ErbB-3 heterodimers and induces cell death of LNCaP cells. By contrast, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers and induces cell growth and survival. Interestingly, LNCaP cells treated with PI3K inhibitor underwent cell death but cells treated with both NRG and PI3K inhibitor survived as the control cells, indicating that the PI3K pathway may mediate NRG-induced cell death. NRG-induced cell death was not inhibited by the broad-spectrum caspases inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK). However, NRG-induced cell death was inhibited by type II cell death inhibitor, 3-methyladenine.


CONCLUSIONS
These results suggest that NRG induces type II cell death of LNCaP cells through PI3K-dependent pathway.
Tal-Or
Pazit
P
Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv, Israel.
Di-Segni
Ayelet
A
Lupowitz
Zipora
Z
Pinkas-Kramarski
Ronit
R
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D020880:Neuregulins / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D002867:Chromones; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D020880:Neuregulins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014443:Tyrosine; C025946:3-methyladenine; D004815:Epidermal Growth Factor; D000225:Adenine