Ferruginol suppresses survival signaling pathways in androgen-independent human prostate cancer cells.
Ferruginol, a bioactive compound isolated from a Chilean tree (Podocarpaceae), attracts attention as a consequence of its pharmacological properties, which include anti-fungal, anti-bacterial, cardioprotective, anti-oxidative, anti-plasmodial and anti-ulcerogenic actions. Nevertheless, the molecular basis for these actions remains only partly understood and hence we investigated the effects of ferruginol on androgen-independent human prostate cancer cells (PC3), a known model for solid tumor cells with an exceptional resistance to therapy. The results show that ferruginol induces PC3 cell death via activation of caspases as well as apoptosis-inducing factor (AIF) as confirmed by its translocation into the nucleus. In order to clarify the biochemical mechanism responsible for the anti-tumor activity of ferruginol, we analyzed a set of molecular mediators involved in tumor cell survival, progression and aggressiveness. Ferruginol was able to trigger inhibition/downregulation of Ras/PI3K, STAT 3/5, protein tyrosine phosphatase and protein kinases related to cell cycle regulation. Importantly, the toxic effect of ferruginol was dramatically impeded in a more reducing environment, which indicates that at least in part, the anti-tumoral activity of ferruginol might be related to redox status modulation. This study supports further examination of ferruginol as a potential agent for both the prevention and treatment of prostate cancer.
Bispo de Jesus
Marcelo
M
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Cidade Universitária, Zeferino Vaz, Barão Geraldo, 13083-970 Campinas, SP, Brazil.
Zambuzzi
Willian Fernando
WF
Ruela de Sousa
Roberta Regina
RR
Areche
Carlos
C
Santos de Souza
Ana Carolina
AC
Aoyama
Hiroshi
H
Schmeda-Hirschmann
Guillermo
G
Rodríguez
Jaime A
JA
Monteiro de Souza Brito
Alba Regina
AR
Peppelenbosch
Maikel P
MP
den Hertog
Jeroen
J
de Paula
Eneida
E
Ferreira
Carmen Veríssima
CV
D045784:Abietanes / Q000737:chemistry / Q000633:toxicity*; D000728:Androgens; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D045784:Abietanes; D000728:Androgens; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D011518:Proto-Oncogene Proteins; D050791:STAT Transcription Factors; C431074:ferruginol; D051550:I-kappa B Kinase; C490429:ACP1 protein, human; D017027:Protein Tyrosine Phosphatases; D020169:Caspases