Neuregulin promotes autophagic cell death of prostate cancer cells

Tal-Or, Pazit; Di-Segni, Ayelet; Lupowitz, Zippora; Pinkas‐Kramarski, Ronit

doi:10.1002/pros.10200

Cited by 19 publications

(23 citation statements)

References 39 publications

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“…However, in prostate cancer, there are conflicting reports as to whether the ErbB4 protein is expressed (43) or not (10) in primary cancers. It has been suggested that NRG1 is able to inhibit prostate cell growth and division (10), induce apoptosis (44) and promote differentiation (45). At this time, it is therefore difficult to suggest hypotheses regarding the role of the NRGs in this disease, but a minimal requirement is to know the components of the system so that experiments that are able to explore this system can be designed.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer

Hayes¹,

Blackburn²,

Smart³

et al. 2007

Clinical Cancer Research

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Purpose: The neuregulin (NRG) 1, 2, and 3 genes undergo extensive alternative mRNA splicing, which results in variants that show structural and functional diversity. The aims of this study were to establish whether the fourth member of this family, NRG4, is expressed in prostate cancer, if it is alternatively spliced and whether any functional differences between the variants could be observed. Experimental Design: The expression of NRG4 was determined using immunohistochemical staining of 40 cases of primary prostate cancer. Bioinformatic analysis and reverse transcription-PCR (RT-PCR) using NRG4 isotype-specific primers on a panel of normal and prostate cancer cell lines were used to identify alternatively spliced NRG4 variants. Expression of these variants was determined using isotype-specific antibodies. Transfection into Cos-7 cells of two of these green fluorescent protein-tagged variants allowed analysis of their subcellular location. Four of the variants were chemically synthesized and tested for their ability to activate the ErbB4 receptor. Results: NRG4 was variably expressed in the cytoplasm in the majority of prostate cancer cases, and in a subset of cases in the membrane, high levels were associated with advanced disease stage. Four novel NRG4 splice variants (NRGA2, NRG4 B1-3) were characterized, where each seemed to have a different subcellular location and were also expressed in the cytoplasm of the prostate tumors. NRG4 B3 was also present in endothelial cells. In transfected cells, the A type variant (NRG4 A1) was localized to the membrane, whereas the B type variant (NRG4 B1), which lacks the predicted transmembrane region, had an intracellular localization. Only the variants with an intact epidermal growth factor^like domain activated ErbB4 signaling. Conclusion: NRG4 overexpression is associated with advanced-stage prostate cancer. The alternative splice variants may have different roles in cell signaling, some acting as classic receptor ligands and some with as-yet unknown functions.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer

Hayes¹,

Blackburn²,

Smart³

et al. 2007

Clinical Cancer Research

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“…For example, activating mutations of ras proto-oncogenes, the most frequently mutated protooncogenes in human tumors, trigger autophagy in glioblastoma as well as colon and gastric cancer cells (Chi et al, 1999;Pattingre et al, 2003). The ability of Ras to cause autophagy may explain the autophagy observed in prostate cancer cells following activation of ErbB2 and ErbB3 (receptor tyroisine kinases that activate Ras pathway) (Tal-Or et al, 2003). Interestingly, one of the signalling pathways regulated by Ras, the Raf-Erk1/2 pathway, triggers autophagy (Pattingre et al, 2003), whereas another downstream arm of Ras signalling, PI3K-PKB pathway, inhibits it (Arico et al, 2001).…”

Section: Promotion and Inhibition Of Pcd During Tumourigenesismentioning

confidence: 99%

Multiple cell death pathways as regulators of tumour initiation and progression

Jäättelä

2004

Oncogene

261

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Acquired defects in signalling pathways leading to programmed cell death (PCD) are among the major hallmarks of cancer. Although focus has been on caspasedependent apoptotic death pathways, evidence is now accumulating that nonapoptotic PCD also can form an important barrier against tumour initiation and progression. Akin to the earlier landmark discoveries that lead to the identification of the major cancer-related proteins like p53, c-Myc and Bcl-2 as controllers of spontaneous and therapy-induced apoptosis, numerous proteins with properties of tumour suppressors and oncoproteins have recently been identified as key regulators of alternative death programmes. The emerging data on the molecular mechanisms regulating nonapoptotic PCD may have potent therapeutic consequences.

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“…EGFR, HER3, and HER4 are activated via ligand binding, which results in the formation of homodimers or heterodimers with other family members (4). As HER2 ligands have not been identified, HER2 is believed to be activated by forming heterodimers with other family members (3,5). Formation of HER receptor homodimers or heterodimers results in receptor activation via tyrosine kinase -mediated autophosphorylation, resulting in phosphorylation and activation of downstream pathways, such as the mitogen-activated protein kinase cascade and the phosphatidylinositol 3-kinase (PI3K)/Akt cascade (6).…”

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confidence: 99%

The Role of HER1-HER4 and EGFRvIII in Hormone-Refractory Prostate Cancer

Edwards

Traynor

Munro

et al. 2006

Clinical Cancer Research

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Purpose: The role of the type I receptor tyrosine kinase (HER) family in progression of prostate cancer is controversial. Breast cancer studies show that these receptors should be investigated as a family. The current study investigates expression of HER1-HER4 and EGFRvIII in matched hormone-sensitive and hormone-refractory prostate tumors. Experimental Design: Immunohistochemical analysis was used to investigate protein expression of HER1-HER4, EGFRvIII, and phosphorylated Akt (pAkt) in matched hormone-sensitive and hormone-refractory prostate tumors. Results: Surprisingly, high HER2 membrane expression in hormone-sensitive tumors was associated with an increased time to biochemical relapse (P = 0.0003), and this translated into longer overall survival (P = 0.0021). Consistent with other studies, HER4 membrane expression in hormone-sensitive tumors was associated with longer time to biochemical relapse (P = 0.042), and EGFRvIII membrane expression was associated with shorter time to biochemical relapse (P = 0.015). An increase in pAkt expression was associated with reduced survival (P = 0.0098). Multivariate analysis showed that HER2 was an independent positive predictive marker of time to relapse in hormone-sensitive prostate tumors (P = 0.014). In contrast, high HER2 expression in hormone-refractory tumors was associated with decreased time to death from biochemical relapse (P = 0.039), and EGFRvIII nuclear expression was associated with decreased time to death from biochemical relapse and decreased overall survival (P = 0.02 and P = 0.005). Conclusion:These results suggest that the HER family may have multiple roles in prostate cancer, and that expression of the proteins alone is insufficient to predict the biological response that they may elicit.

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Neuregulin promotes autophagic cell death of prostate cancer cells

Abstract: These results suggest that NRG induces type II cell death of LNCaP cells through PI3K-dependent pathway.

Cited by 19 publications

References 39 publications

Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer

Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer

Multiple cell death pathways as regulators of tumour initiation and progression

The Role of HER1-HER4 and EGFRvIII in Hormone-Refractory Prostate Cancer

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