Oxidant species including Reactive oxygen species (ROS) play a vital role in mediating diverse cellular signalling and apoptosis in normal cells. Excess oxidant species can oxidize numerous vital molecules to promote the development and progression of many cancers. While there are numerous studies on the correlative influence of oxidant species on cancer progression, the effect of oxidant species and its molecular mechanism by a specific oxidase/pro-oxidant protein of clinical relevance on cancer progression remains investigation.
Using prostate cancer (PCa) as a model system, we investigate p66Shc protein’s role in the progression of advanced castration-resistant (CR) phenotype, a lethal PCa. p66Shc, a member of Src homologue and collagen homologue family, can interact with Cytochrome C in mitochondria and via Rac 1 with NAD(P)H oxidases (NOXs) in cytosol for enhancing oxidant species production. In clinical archival specimens, p66Shc protein is significantly elevated in cancerous cells. Upon cDNA transfection, increased expression of the wild type p66Shc protein, but not inactive mutant, via oxidant species production supports PCa cells to obtain the CR phenotype in androgen-deprived conditions and metastasis in xenograft tumors. Hence, p66Shc and its downstream signaling molecules can serve as effective therapeutic targets for treating the patient sub-population with cancers of prostate, colon, breast, ovarian, thyroid and other types.
Dr. Lin is Professor and Vice-Chair for Research in the Department of Biochemistry and Molecular Biology, UNMC, USA. Dr. Lin is a veteran in prostate cancer (PCa) biology research with over 30 years’ experience and performed initial biochemical characterizations of PCa biomarkers, prostate-specific antigen and prostatic acid phosphatase, under Dr. T. Ming Chu’s guidance. The ultimate goal of Dr. Lin’s research is to reduce cancer-related death.
Over his career, Dr. Lin is recognized by peers as a leading expert in investigating the integration of signaling pathways involved in castration-resistant (CR) PCa. Dr. Lin made the first seminal observation on the cross-talk between androgens and tyrosine phosphorylation signaling. Dr. Lin further discovered that cellular prostatic acid phosphatase (cPAcP) functions as a PTEN-functional homologue with tumor suppressor activity and is involved in regulating androgen sensitivity, a hallmark of PCa. By knockdown cPAcP, androgen-sensitive cells obtain the CR phenotype, corroborating the loss of cPAcP expression in clinical carcinomas. Dr. Lin then discovered that elevated p66Shc protein as seen in clinical specimens enhances oxidant species production, PCa progression and tumorigenecity, in part by inhibiting cPAcP under androgen-deprived conditions. His lab is currently elucidating the novel, dynamic integration via androgen, p66Shc/ROS and tyrosine phosphorylation in CR PCa progression. In parallel, Dr. Lin is a leading expert in investigating neuroendocrine transdifferentiation.