Gene expression profiling revealed novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells.
Both docetaxel and estramustine are antimicrotubule agents with antitumor activity in various cancers including prostate cancer. Clinical trials for docetaxel and estramustine combination treatment have suggested improved antitumor activity in hormone-refractory prostate cancer. However, the molecular mechanisms involved in the combination treatment with docetaxel and estramustine have not been fully elucidated. In order to establish such molecular mechanisms in both hormone insensitive (PC-3) and sensitive (LNCaP) prostate cancer cells, gene expression profiles of docetaxel- and estramustine-treated prostate cancer cells were obtained by using Affymetrix Human Genome U133A Array. Total RNA from PC-3 and LNCaP cells untreated and treated with 2 nmol/L docetaxel, 4 micromol/L estramustine, or 1 nmol/L docetaxel plus 2 micromol/L estramustine for 6, 36, and 72 hours was subjected to microarray analysis. Real-time PCR and Western blot analysis were conducted to confirm the microarray data. Clustering analysis based on biological function showed that docetaxel and estramustine combination treatment down-regulated some genes that are known to regulate cell proliferation, transcription, translation, and oncogenesis. In contrast, docetaxel and estramustine combination treatment up-regulated some genes related to induction of apoptosis, cell cycle arrest, and tumor suppression. Docetaxel and estramustine also showed differential effects on gene expression between mono- and combination treatment. Combination treatment with docetaxel and estramustine caused alternations of a large number of genes, many of which may contribute to the molecular mechanisms by which docetaxel and estramustine inhibit the growth of prostate cancer cells. These results provide novel molecular targets of docetaxel and estramustine combination treatment in prostate cancer cells. This information could be utilized for further mechanistic research and for devising optimized therapeutic strategies against prostate cancer.
Li
Yiwei
Y
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 715 Hudson Webber Cancer Research Center, 110 East Warren, Detroit, MI 48201, USA.
Hong
Xin
X
Hussain
Maha
M
Sarkar
Sarah H
SH
Li
Ran
R
Sarkar
Fazlul H
FH
D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018076:DNA, Complementary / Q000378:metabolism; D000077143:Docetaxel; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004961:Estramustine / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D012333:RNA, Messenger; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine