Effect of zinc on regulation of insulin-like growth factor signaling in human androgen-independent prostate cancer cells.
BACKGROUND
Prostate cancer is one of the most frequently diagnosed cancers in men. Progression of these tumors is facilitated by growth factors that activate critical signaling cascades thereby promote prostate cancer cell growth, survival, and migration. Among these, insulin-like growth factors (IGFs) signaling pathway contributes a major role. In this study, we examined the effect of zinc on insulin-like growth factors signaling in prostate cancer cells.


METHODS
Human androgen-independent prostatic carcinoma (PC-3) cells were treated with different concentrations of zinc (20-100micromol/l) for 24 and 48h. Cell viability was performed by 3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Insulin-like growth factor binding protein-3 (IGFBP-3), insulin-like growth factor-I receptor (IGF-IR), insulin receptor substrate-1 (IRS-1) and IRS-2, phosphatidylinositol-3 kinase (PI-3 K), protein kinase B or Akt, phosphorylated Akt (p-Akt), extracellular regulated kinase 1/2 (ERK1/2), phosphorylated ERK1/2 (p-ERK1/2), and cyclin D1 protein levels were assessed by Western blot analysis. Apoptosis was confirmed by 4',6'-diaminido-2-phenylindole dihydrochloride (DAPI) staining, and mitochondrial membrane potential was performed using rhodamine-123 staining method.


RESULTS
Zinc significantly reduces the cell viability of PC-3 cells. It decreases the protein levels of IGF-IR, IRS-1, and IRS-2 and increases the level of IGFBP-3. Zinc reduces the levels of PI-3 K, Akt, ERK1/2, and cyclin Dl. Loss of mitochondrial membrane potential and apoptotic cell death were also observed in zinc-treated cells.


CONCLUSIONS
This study suggests that zinc decreases the survival of androgen-independent prostate cancer cells by modulating the expression of IGF system components and its signaling molecules. Thus, zinc may be qualified as a potential agent for the treatment of prostate cancer.
Banudevi
Sivanantham
S
Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai - 600113, Tamilnadu, India.
Senthilkumar
Kalimuthu
K
Sharmila
Govindaraj
G
Arunkumar
Ramachandran
R
Vijayababu
Marati Radhakrishnan
MR
Arunakaran
Jagadeesan
J
D000728:Androgens / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013002:Somatomedins / Q000378:metabolism*; D013194:Staining and Labeling; D015032:Zinc / Q000494:pharmacology*
D000728:Androgens; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D013002:Somatomedins; D019938:Cyclin D1; C007293:DAPI; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015032:Zinc