Yi Lu, Ph.D., Assistant Professor
 Department of Medicine

A novel gene, rat pHyde, and its human homologue, hpHyde, have been cloned from prostate cancer cells. A recombinant adenovirus containing rat pHyde cDNA gene showed significant growth inhibition on human prostate cancer cells both in vitro and in vivo, and induced a caspase-3 dependent apoptosis. Database search and FISH analysis consistently indicated that hpHyde gene localizes at human chromosome 2q14. Protein sequence analysis suggests that hpHyde is a plasma membrane protein that may have calcium channel function. Immunohistochemistry revealed a differential expression of hpHyde protein in normal and cancerous prostate tissues. hpHyde also differentially expressed in various normal human tissues, suggesting that hpHyde may play roles in development and differentiation. Taken together, these results suggest that a novel apoptosis-inducing gene, hpHyde, may play important roles in normal prostate development and prostate carcinogenesis. Studies of biological and physiological functions of this novel gene may elucidate new signal transduction pathway in prostate biology and provide potential therapeutic approach for prostate cancer treatment.

Blocking tumor angiogenesis may be an effective approach to suppress tumor metastasis. Vascular endothelial growth factor (VEGF) plays a pivotal role in tumor angiogenesis. The degree of tumor malignancy correlates with the expression of VEGF and the inverse expression of tumor suppressor gene p16. To examine whether p16 decreases VEGF gene expression and inhibits tumor angiogenesis and metastasis in breast cancer cells, human breast cancer cell line MDA-MB-231, MCF-7 and mouse breast cancer cell line JygMC(A) were transduced with recombinant adenovirus expressing human wild-type p16 (AdRSVp16). Our study showed that adenoviral-mediated p16 expression downregulated VEGF signaling pathway at both ligand and receptor levels, and inhibited in vitro cell growth in breast cancer cells. AdRSVp16 attenuated in vivo angiogenesis induced by MDA-MB-231 cells, and suppressed spontaneous metastasis of JygMC(A) cells to lung and liver in nude mice after subcutaneous injection. These results together strongly suggest that impairing of VEGF signaling pathway by p16 leads suppression of breast tumor angiogenesis and metastasis. Therefore, the viral vector-based p16 gene therapy may have clinical potentials to suppress breast cancer growth and metastasis

Recent Publications

Wang Y, Zhang Y, Steiner MS, and Lu Y. p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. Oncogene 19:1297-1306, 2000.

Steiner MS, Zhang X, Wang Y, and Lu Y. Growth inhibition of prostate cancer by adenovirus expressing a novel tumor suppressor gene pHyde. Cancer Research 60:4419-4425, 2000.

Zhang Y, Farooq F, Lerner J, Wang Y, Steiner MS, and Lu Y. Adenoviral vector containing wild type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence. Cancer Gene Ther 7:360-372, 2000.

Lu Y. Viral-based gene therapy for prostate cancer. Current Gene Ther 1:183-200, 2001.

Zhang X, Steiner MS, Rinaldy A, and Lu Y. Apoptosis induction in prostate cancer cells by a novel gene protein product, pHyde, involves casapase-3. Oncogene 20:5982-5990, 2001.

Weld KJ, Mayher BE, Allay JA, Randolph MM, Lu Y, Steiner MS, and Gingrich JR. Transrectal gene therapy of the prostate in the canine model. Cancer Gene Ther 9:189-196, 2002.

Lu Y, Zhang J, Beech DJ, Myers LK, and Jennings LK. p16 downregulates VEGF and inhibits angiogenesis in breast cancer cells. Cancer Ther 1:143-151, 2003.

 

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