- Basic and translational endocrinology
- Melatonin signaling and translational use of melatonin in prostate cancer therapy
- Targeting autocrine sPDZD2 signaling for tumor suppression
After graduating in Medicine with Honors at The University of Hong Kong (HKU) in 1987 and completing his internship training in 1988, Stephen Shiu pursued his postgraduate study in Oxford University, where he obtained his DPhil degree in 1991.
He then undertook clinical training in microbiology and internal medicine, before he joined the Department of Physiology at HKU in 1995. In 1998, Shiu received the University Teaching Award (University Teaching Fellow) as a recognition of his excellence as a teacher.
His laboratory focuses on unraveling the signaling mechanisms of the neurohormone melatonin and the development of melatonin for prostate cancer prevention and treatment.
Prostate cancer is the most common cancer in men, and the second most common cause of cancer deaths among men in developed countries. There is an unmet clinical need for safe and effective drugs that can prevent or slow the development and progression of the disease. Melatonin, a circadian and seasonal hormone produced and secreted by the pineal gland, modulates biorhythms and inhibits cancer growth. An inverse relationship between melatonin production and human prostate cancer incidence has been shown by epidemiological and clinical studies, which suggested a potential prostate tumor suppressive function of melatonin. Over the years, the aforementioned circumstantial evidence provided by epidemiological and clinical studies was corroborated by laboratory and clinical data of Shiu’s research team, who had demonstrated melatonin MT1 receptor expression in human prostate cancer tissues, and an antiproliferative action of melatonin on prostate cancer xenograft in nude mice. Of note, subsequent administration of melatonin by Shiu and his colleagues to a castrated prostate cancer patient, whose prostate tumor tissue expressed MT1 receptor, was found to slow the early biochemical progression of this patient’s castration-resistant tumor. This proof-of-concept translational study in a human subject indicates that the MT1receptor plays a crucial role in transducing the direct suppressive action of melatonin on prostate cancer. Using androgen receptor-positive LNCaP, 22Rv1, VCaP and RWPE-1 prostate epithelial cell models, Shiu’s research team then successfully delineated the major antiproliferative signaling pathways in prostate tumor cells which are activated by MT1 receptor stimulation. Based on their results, Shiu proposes that melatonin, a small, non-toxic and non-patentable molecule, is a promising drug candidate for prostate cancer chemoprevention, and that androgen depletion and melatonin repletion (ADMR) is a novel strategy in castration-resistant prostate cancer therapy which deserves further testing in clinical trials. Besides melatonin, Shiu and his collaborator have also identified a novel action of the human secreted PDZ domain-containing protein 2 (sPDZD2) in suppressing prostate tumor growth, on which a US patent has been granted.
Changes in ('actual' and 'projected') total PSA of a castration-resistant prostate cancer patient during melatonin treatment
2[125I]iodomelatonin binding to the prostate cancer cell membrane preparations of the index patient
Expression of MT1, MT2 and androgen receptors in prostatic tissue showing nodular hyperplasia
Schematic diagram showing the signaling pathways involved in melatonin receptor-mediated antiproliferation of prostate cancer cells
- Liu VWS, Yau WL, Tam CW, Yao KM, Shiu SYW*. Melatonin inhibits androgen receptor splice variant-7 (AR-V7)-induced nuclear factor-kappa B (NF-kB) activation and NF-kB activator-induced AR-V7 expression in prostate cancer cells: potential implications for the use of melatonin in castration-resistant prostate cancer (CRPC) therapy. Int J Mol Sci 2017; 18, 1130; doi: 10.3390/ijms18061130.
- Shiu SYW*, Leung WY, Tam CW, Liu VWS, Yao KM. Melatonin MT1 receptor-induced transcriptional up-regulation of p27Kip1 in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-kB): potential implications on prostate cancer chemoprevention and therapy. J Pineal Res 2013; 54: 69-79.
- Tam CW, Shiu SYW*. Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: potential implications for therapeutic strategies against prostate cancer. J Pineal Res 2011; 51: 297-312.
- Shiu SYW*, Pang B, Tam CW, Yao KM. Signal transduction of receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Gas and Gaq proteins. J Pineal Res 2010; 49: 301-311.
- Tam CW, Chan KW, Liu VWS, Pang B, Yao KM, Shiu SYW*. Melatonin as a negative mitogenic hormonal regulator of human prostate epithelial cell growth: potential mechanisms and clinical significance. J Pineal Res 2008; 45: 403-412.
- Tam CW, Mo CW, Yao KM, Shiu SYW*. Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention. J Pineal Res 2007; 42: 191-202.
- Tam CW, Cheng AS, Ma RY, Yao KM*, Shiu SYW*. Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor. Endocrinology 2006; 147: 5023-5033.
- Shiu SYW*, Law IC, Lau KW, Tam PC, Yip AWC, Ng WT. Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype. J Pineal Res 2003, 35: 177-182.
- Siu SWF, Lau KW, Tam PC, Shiu SYW*. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate 2002; 52: 106-122. [Erratum, Prostate 2002; 52:252].
- Xi SC, Siu SWF, Fong SW, Shiu SYW*. Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Prostate 2001; 46: 52-61.
- ITF project: Molecular cloning of the cellular receptor for the autocrine tumor suppressor secreted PDZ Domain-containing Protein 2 (sPDZD2)
- University Teaching Fellow (1997-1998)
Shiu SYW, Yao KM. Tumor suppressor protein and nucleotide encoding same. US Patent No.: US7,807,626 B2; Date of Patent: Oct. 5, 2010.