Publications (2)3.01 Total impact
Article: Stable alterations of CD44 isoform expression in prostate cancer cells decrease invasion and growth and alter ligand binding and chemosensitivity.[show abstract] [hide abstract]
ABSTRACT: Dysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses the novel splice variant isoform, CD44v7-10. Using retroviral gene delivery to PC-3M PCa cells, we expressed luciferase-only, enforced CD44s re-expression as a fusion protein with luciferase at its C-terminus or as a protein separate from luciferase, or knocked down CD44v7-10 by RNAi. Invasion, migration, proliferation, soft agar colony formation, adhesion, Docetaxel sensitivity, and xenograft growth assays were carried out. Expression responses of merlin, a CD44 binding partner, and growth-permissive phospho-merlin, were assessed by western blot. Compared to luciferase-only PC-3M cells, all three treatments reduced invasion and migration. Growth and soft agar colony formation were reduced only by re-expression of CD44s as a separate or fusion protein but not CD44v7-10 RNAi. Hyaluronan and osteopontin binding were greatly strengthened by CD44s expression as a separate protein, but not a fusion protein. CD44v7-10 RNAi in PC-3M cells caused marked sensitization to Docetaxel; the two CD44s re-expression approaches caused minimal sensitization. In limited numbers of mouse subcutaneous xenografts, all three alterations produced only nonsignificant trends toward slower growth compared with luciferase-only controls. The expression of CD44s as a separate protein, but not a fusion protein, caused emergence of a strongly-expressed, hypophosphorylated species of phospho-merlin. Stable re-expression of CD44s reduces PCa growth and invasion in vitro, and possibly in vivo, suggesting CD44 alterations have potential as gene therapy. When the C-terminus of CD44s is fused to another protein, most phenotypic effects are lessened, particularly hyaluronan adhesion. Finally, CD44v7-10, although it was not functionally significant for growth, may be a target for chemosensitization.BMC Cancer 01/2010; 10:16. · 3.01 Impact Factor
Article: Dutasteride prevents the growth response to testosterone in benign and androgen-sensitive malignant prostate cells.[show abstract] [hide abstract]
ABSTRACT: We show that the dual 5-α reductase enzyme inhibitor dutasteride prevents enhanced growth of both benign and malignant prostate cell lines, incubated with physiologic to supraphysiologic doses of testosterone. Using androgen-sensitive benign BPH-1 cells, LNCaP cancer cells, their derivative C4-2 cells, or Dunning rat cancer cells, we subjected 30,000 cells/well to concomitant treatment with 10(-9), 10(-8), or 10(-7) M testosterone in the presence of low (0.25 μM) or high (1.0 μM) doses of dutasteride. Both low- and high-dose dutasteride abrogated testosterone-stimulated growth of all 4 cell lines. If the in vitro data mimic conditions in men undergoing testosterone replacement, concomitant dutasteride use might make testosterone safe for men with benign prostatic hypertrophy, latent prostate cancer and perhaps even aggressive prostate cancer. Testosterone might also be used to prevent the rare anti-androgen side effects of dutasteride when used for benign prostatic hypertrophy and baldness. Further clinical investigation is indicated.International journal of clinical and experimental medicine 01/2010; 3(3):245-7.