Incubation with somatostatin, 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells.
Somatostatin (SMS), binds to its specific receptors (SSTRs) and transduces growth inhibitory, anti-secretory and apoptotic signals. Several human cancers express SSTRs, including prostate cancer, and therefore SMS is of interest for anti-cancer therapy. DNA methylation and histone modifications are involved in normal cell development, gene imprinting and human carcinogenesis. Reversing DNA methylation is an attractive therapeutic possibility, since epigenetic modifications change gene expression without changing the gene function. DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (5'-aza, decitabine) have been used to treat several types of haematological malignancies. Histone deacetylase inhibitors such as trichostatin (TSA), are a new class of 'targeted anti-cancer agents'. TSA and decitabine can induce growth arrest, apoptosis or terminal differentiation in a variety of solid and haematological cancers in advanced disease patients. In the present study, the LNCaP cell line (prostate cancer) was incubated with SMS or Somadex (an SMS polymer conjugate) for three days, 1 nM per day, and the untreated cells were the negative control. For DNA demethylation, cells were grown in the presence of 2.5 microM 5-aza for 120 h, and re-fed with 5-aza-containing fresh medium at day 3. The total incubation time with 5-aza was 120 h. TSA at 1.0 microM was added into the cultured cells for 24 h. The combined treatment of 5-aza and TSA was performed by incubating the cells with 5-aza for 120 h followed by a 24-h exposure to TSA. Using cDNA obtained from these cell lines, the difference in the expression level of SSTR mRNA transcripts before and after 5-aza and TSA treatments was analyzed by RT-PCR. An increased induction of mRNA expression of the five SSTR subtypes was observed in the LNCaP cells when incubated with SMS/Somadex (dose-dependent). The inhibition of DNA methylation and histone acetylation resulted in the up-regulation of SSTR5 mRNA expression. The results demonstrate a positive feedback loop between SMS and its receptors. This regulation pathway may enhance the anti-tumor activity of somatostatin. To benefit from this effect in a clinical setting, the dose, dose frequency and pan affinity of the SMS derivative are important factors. The epigenetic manipulation with DNA methylation or histone deacetylase inhibitors, combined with SMS, may offer a novel alternative for the treatment of advanced prostate cancer.
Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
Zhaoxu
Z
Liu
Marcela
M
Marquez
Sten
S
Nilsson
Anders R
AR
Holmberg
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D017481:Receptors, Somatostatin / Q000235:genetics*; D013004:Somatostatin / Q000494:pharmacology*; D015854:Up-Regulation
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C012589:trichostatin A; D013004:Somatostatin; D000077209:Decitabine; D001374:Azacitidine