Bio

Honors & Awards


  • PC094637, DOD (2010-2012)

Professional Education


  • Bachelor of Science, National Taiwan University (2003)
  • Master of Science, National Cheng Kung University (2005)
  • Doctor of Philosophy, University of Rochester (2012)

Stanford Advisors


Publications

Journal Articles


  • Exposure of polyethylene particles induces interferon-gamma expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: A preliminary study JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Lin, T., Kao, S., Sato, T., Pajarinen, J., Zhang, R., Loi, F., Goodman, S. B., Yao, Z. 2015; 103 (1): 71-75
  • Mutant monocyte chemoattractant protein 1 protein attenuates migration of and inflammatory cytokine release by macrophages exposed to orthopedic implant wear particles. Journal of biomedical materials research. Part A Yao, Z., Keeney, M., Lin, T., Pajarinen, J., Barcay, K., Waters, H., Egashira, K., Yang, F., Goodman, S. 2014; 102 (9): 3291-3297

    Abstract

    Wear particles generated from total joint replacements can stimulate macrophages to release chemokines, such as monocyte chemoattractant protein 1 (MCP-1), which is the most important chemokine regulating systemic and local cell trafficking and infiltration of monocyte/macrophages in chronic inflammation. One possible strategy to curtail the adverse events associated with wear particles is to mitigate migration and activation of monocyte/macrophages. The purpose of this study is to modulate the adverse effects of particulate biomaterials and inflammatory stimuli such as endotoxin by interfering with the biological effects of the chemokine MCP-1. In the current study, the function of MCP-1 was inhibited by the mutant MCP-1 protein called 7ND, which blocks its receptor, the C-C chemokine receptor type 2 (CCR2) on macrophages. Addition of 7ND decreased MCP-1-induced migration of THP-1 cells in cell migration experiments in a dose-dependent manner. Conditioned media from murine macrophages exposed to clinically relevant polymethylmethacrylate (PMMA) particles with/without endotoxin [lipopolysaccharide (LPS)] had a chemotactic effect on human macrophages, which was decreased dramatically by 7ND. 7ND demonstrated no adverse effects on the viability of macrophages, and the capability of mesenchymal stem cells (MSCs) to form bone at the doses tested. Finally, proinflammatory cytokine production was mitigated when macrophages were exposed to PMMA particles with/without LPS in the presence of 7ND. Our studies confirm that the MCP-1 mutant protein 7ND can decrease macrophage migration and inflammatory cytokine release without adverse effects at the doses tested. Local delivery of 7ND at the implant site may provide a therapeutic strategy to diminish particle-associated periprosthetic inflammation and osteolysis. 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

    View details for DOI 10.1002/jbm.a.34981

    View details for PubMedID 24123855

  • Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-?B decoy oligodeoxynucleotide: A preliminary report. Acta biomaterialia Lin, T., Yao, Z., Sato, T., Keeney, M., Li, C., Pajarinen, J., Yang, F., Egashira, K., Goodman, S. B. 2014; 10 (8): 3747-3755

    Abstract

    Total joint replacement (TJR) is a very cost-effective surgery for end-stage arthritis. One important goal is to decrease the revision rate especially because TJR has been extended to younger patients. Continuous production of ultra-high molecular weight polyethylene (UHMWPE) wear particles induces macrophage infiltration and chronic inflammation, which can lead to peri-prosthetic osteolysis. Targeting individual pro-inflammatory cytokines directly has not reversed the osteolytic process in clinical trials, due to compensatory upregulation of other pro-inflammatory factors. We hypothesized that targeting the important transcription factor NF-?B could mitigate the inflammatory response to wear particles, potentially diminishing osteolysis. In the current study, we suppressed NF-?B activity in mouse RAW264.7 and human THP1 macrophage cell lines, as well as primary mouse and human macrophages, via competitive binding with double strand decoy oligodeoxynucleotide (ODN) containing an NF-?B binding element. We found that macrophage exposure to UHMWPE particles induced multiple pro-inflammatory cytokine and chemokine expression including TNF-?, MCP1, MIP1? and others. Importantly, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, and resulted in suppression of macrophage recruitment. The strategic use of decoy NF-?B ODN, delivered locally, could potentially diminish particle-induced peri-prosthetic osteolysis.

    View details for DOI 10.1016/j.actbio.2014.04.034

    View details for PubMedID 24814879

  • Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. Journal of the Royal Society, Interface / the Royal Society Goodman, S. B., Gibon, E., Pajarinen, J., Lin, T., Keeney, M., Ren, P., Nich, C., Yao, Z., Egashira, K., Yang, F., KONTTINEN, Y. T. 2014; 11 (93): 20130962-?

    Abstract

    Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-?B) by delivery of an NF-?B decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.

    View details for DOI 10.1098/rsif.2013.0962

    View details for PubMedID 24478281

  • NF-?B Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle. Tissue engineering. Part A Lin, T. H., Sato, T., Barcay, K. R., Waters, H., Loi, F., Zhang, R., Pajarinen, J., Egashira, K., Yao, Z., Goodman, S. B. 2014

    Abstract

    Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-?B in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultra-high molecular weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF-?B signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased TGF-?1 and osteoprotegerin in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN up-regulated osteoprotegerin expression through a TGF-?1 dependent pathway. By measuring alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regards to cell phenotype, cell viability and osteogenic ability were confirmed using primary human MSCs. Our results suggest that modulation of wear particle induced inflammation by NF-?B decoy ODN had no adverse effects on MSCs, and may potentially further mitigate peri-prosthetic osteolysis by protecting MSC viability and osteogenic ability.

    View details for DOI 10.1089/ten.TEA.2014.0144

    View details for PubMedID 25518013

  • Modulation of mouse macrophage polarization in vitro using IL-4 delivery by osmotic pumps. Journal of biomedical materials research. Part A Pajarinen, J., Tamaki, Y., Antonios, J. K., Lin, T. H., Sato, T., Yao, Z., Takagi, M., Konttinen, Y. T., Goodman, S. B. 2014

    Abstract

    Modulation of macrophage polarization is emerging as promising means to mitigate wear particle-induced inflammation and periprosthetic osteolysis. As a model for continuous local drug delivery, we used miniature osmotic pumps to deliver IL-4 in order to modulate macrophage polarization in vitro from nonactivated M0 and inflammatory M1 phenotypes towards a tissue regenerative M2 phenotype. Pumps delivered IL-4 into vials containing mouse bone marrow macrophage (mBMM) media. This conditioned media (CM) was collected at seven day intervals up to four weeks (week 1 to week 4 samples). IL-4 concentration in the CM was determined by ELISA and its biological activity was assayed by exposing M0 and M1 mBMMs to week 1 or week 4 CM. The IL-4 concentration in the CM approximated the mathematically calculated amount, and its biological activity was well retained, as both M0 and M1 macrophages exposed to either the week 1 or week 4 CM assumed M2-like phenotype as determined by qRT-PCR, ELISA, and immunocytochemistry. The results show that IL-4 can be delivered using osmotic pumps and that IL-4 delivered can modulate macrophage phenotype. Results build a foundation for in vivo studies using our previously validated animal models and provide possible strategies to locally mitigate wear particle-induced macrophage activation and periprosthetic osteolysis. 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2014.

    View details for DOI 10.1002/jbm.a.35278

    View details for PubMedID 25044942

  • The wedelolactone derivative inhibits estrogen receptor-mediated breast, endometrial, and ovarian cancer cells growth. BioMed research international Xu, D., Lin, T. H., Yeh, C. R., Cheng, M. A., Chen, L. M., Chang, C., Yeh, S. 2014; 2014: 713263

    Abstract

    Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5??M BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

    View details for DOI 10.1155/2014/713263

    View details for PubMedID 25221777

  • Exposure of Polyethylene Particles Induces Interferon-? Expression in a Natural Killer T Lymphocyte and Dendritic Cell Co-Culture System in vitro: A Preliminary Study. Journal of biomedical materials research. Part A Lin, T. H., Kao, S., Taishi, S., Pajarenin, J., Zhang, R., Loi, F., Goodman, S. B., Yao, Z. 2014

    Abstract

    Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-? (IFN-?); co-culture with DCs further enhanced IFN-? secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand ? -Galactosylceramide (?-GalCer) treatment in the co-culture system significantly enhanced both IFN-? and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate Interferon-? or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased TNF-?, but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.

    View details for DOI 10.1002/jbm.a.35159

    View details for PubMedID 24616165

  • Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-?B as a therapeutic target. Acta biomaterialia Lin, T., Tamaki, Y., Pajarinen, J., Waters, H. A., Woo, D. K., Yao, Z., Goodman, S. B. 2014; 10 (1): 1-10

    Abstract

    Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-?B. NF-?B activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-?, IL-1?, IL-6 and MCP1. In addition, NF-?B activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-? or IL-1?) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core I?B/IKK?/?/NF-?B signaling pathway in the local environment. However, the timing, dose and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-?B activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

    View details for DOI 10.1016/j.actbio.2013.09.034

    View details for PubMedID 24090989

  • Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis HEPATOLOGY Huang, C., Lee, S. O., Lai, K., Ma, W., Lin, T., Tsai, M., Luo, J., Chang, C. 2013; 57 (4): 1550-1563

    Abstract

    Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat liver cirrhosis, an irreversible disease that may eventually lead to liver cancer development. However, low survival rate of the BM-MSCs leading to unsatisfactory efficacy remains a major concern. Gender differences have been suggested in BM-MSCs therapeutic application, but the effect of the androgen receptor (AR), a key factor in male sexual phenotype, in this application is not clear. Using two liver cirrhosis mouse models induced by CCl4 or thioacetamide, we showed that targeting AR in the BM-MSCs improved their self-renewal and migration potentials and increased paracrine effects to exert anti-inflammatory and anti-fibrotic actions to enhance liver repair. Mechanism dissection studies suggested that knocking out AR in BM-MSCs led to improved self-renewal and migration by alteration of the signaling of epidermal growth factor receptor and matrix metalloproteinase 9 and resulted in suppression of infiltrating macrophages and hepatic stellate cell activation through modulation of interleukin (IL)1R/IL1Ra signaling. Therapeutic approaches using either AR/small interfering RNA or the AR degradation enhancer, ASC-J9, to target AR in BM-MSCs all led to increased efficacy for liver repair.Targeting AR, a key factor in male sexual phenotype, in BM-MSCs improves transplantation therapeutic efficacy for treating liver fibrosis.

    View details for DOI 10.1002/hep.26135

    View details for Web of Science ID 000317363600028

    View details for PubMedID 23150236

  • New therapy targeting differential androgen receptor signaling in prostate cancer stem/progenitor vs. non-stem/progenitor cells JOURNAL OF MOLECULAR CELL BIOLOGY Lee, S. O., Ma, Z., Yeh, C., Luo, J., Lin, T., Lai, K., Yamashita, S., Liang, L., Tian, J., Li, L., Jiang, Q., Huang, C., Niu, Y., Yeh, S., Chang, C. 2013; 5 (1): 14-26

    Abstract

    The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and ?-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.

    View details for DOI 10.1093/jmcb/mjs042

    View details for Web of Science ID 000315223900003

    View details for PubMedID 22831834

  • Differential Androgen Deprivation Therapies with Anti-androgens Casodex/Bicalutamide or MDV3100/Enzalutamide versus Anti-androgen Receptor ASC-J9(R) Lead to Promotion versus Suppression of Prostate Cancer Metastasis. The Journal of biological chemistry Lin, T. H., Lee, S. O., Niu, Y., Xu, D., Liang, L., Li, L., Yeh, S. D., Fujimoto, N., Yeh, S., Chang, C. 2013; 288 (27): 19359-69

    Abstract

    Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9 and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 ?m Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9 led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-?1/Smad3/MMP9 pathway, but ASC-J9 and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9 to battle PCa metastasis at the castration-resistant stage.

    View details for PubMedID 23687298

  • Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell death & disease Lin, T., Izumi, K., Lee, S. O., Lin, W., Yeh, S., Chang, C. 2013; 4

    Abstract

    Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

    View details for DOI 10.1038/cddis.2013.270

    View details for PubMedID 23928703

  • The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells PROSTATE Xu, D., Lin, T., Zhang, C., Tsai, Y., Li, S., Zhang, J., Yin, M., Yeh, S., Chang, C. 2012; 72 (7): 803-816

    Abstract

    Androgen receptor (AR) is the main therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy (ADT) is only effective for a short period of time. Here we tested PTS33, a new sodium derivative of cryptotanshinone, which can effectively inhibit the DHT-induced AR transactivation and PCa cell growth, and then explored the effects of PTS33 on inhibiting the expressions of AR target genes and proteins.PCa cells, LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with PTS33 and luciferase assay was used to evaluate the ability of each to regulate AR transactivation. RT-PCR was used to evaluate the mRNA levels of AR target genes such as PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR, PSA, estrogen receptor alpha (ER?), glucocorticoid receptor (GR), and progesterone receptor (PR) protein expression. Cell growth and IC50 were determined by MTT assay after 48?hr treatment.Our data showed that PTS33 selectively inhibits AR activities, but PTS33 does not repress the activities of other nuclear receptors, including ER?, GR, and PR. At a low concentration, 2?M of PTS33 effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Furthermore, our data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 can also inhibit estrogen/?5-androstenediol induced AR activities. The mechanistic studies indicate that PTS33 can inhibit AR function by suppression of AR protein expression, the AR N-C interaction, and AR-coregulator interaction.PTS33 has shown a good efficacy to inhibit AR transactivation, block AR regulated gene expression, and reduce cell growth in AR positive PCa cells. The structure of PTS33 could be used as a base for development of novel AR signaling inhibitors to treat PCa.

    View details for DOI 10.1002/pros.21474

    View details for Web of Science ID 000303197200012

    View details for PubMedID 21932429

  • Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells CANCER LETTERS Xu, D., Lin, T., Li, S., Da, J., Wen, X., Ding, J., Chang, C., Yeh, S. 2012; 316 (1): 11-22

    Abstract

    Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 ?M CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selectively inhibits AR without repressing the activities of other nuclear receptors, including ER?, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.

    View details for DOI 10.1016/j.canlet.2011.10.006

    View details for Web of Science ID 000299712400003

    View details for PubMedID 22154085

  • A Positive Feedback Signaling Loop between ATM and the Vitamin D Receptor Is Critical for Cancer Chemoprevention by Vitamin D CANCER RESEARCH Ting, H., Yasmin-Karim, S., Yan, S., Hsu, J., Lin, T., Zeng, W., Messing, J., Sheu, T., Bao, B., Li, W. X., Messing, E., Lee, Y. 2012; 72 (4): 958-968

    Abstract

    Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1?,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR.

    View details for DOI 10.1158/0008-5472.CAN-11-0042

    View details for Web of Science ID 000300629100015

    View details for PubMedID 22207345

  • Tissue-specific knockout of androgen receptor in mice. Methods in molecular biology (Clifton, N.J.) Lin, T., Yeh, S., Chang, C. 2011; 776: 275-293

    Abstract

    Androgen acting through the androgen receptor (AR) is known to be essential for male sexual differentiation and development. Using Cre-lox technology, we have generated the floxed AR mice, which have been bred with general or tissue-specific Cre expressing transgenic mice to knock out the AR gene in specific target cells. Our findings indicated that AR is required for sexual development and that loss of AR can have significant effects on many aspects of physiological functions and disease progression, such as immune function, metabolism, and tumorigenesis. Furthermore, our strategy can generate AR knockout (ARKO) in female mice, which allows researchers to study the AR function in the female. In brief, our floxed AR mouse model provides a powerful tool to study in vivo AR functions in selective tissues and cell types and has made possible several research breakthroughs in the field of endocrinology.

    View details for DOI 10.1007/978-1-61779-243-4_16

    View details for PubMedID 21796532

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