 |
Janet Houghton, Ph.D.Department ChairThe Betsy B. de Windt Endowed Chair in Cancer BiologyDepartment of Cancer Biology |
Area of general research interest:
Developmental therapeutics, death receptor signaling and therapeutic response, human tumor xenograft models, translational research
Current program:
- Investigation of death receptor signaling in solid tumors, with an emphasis in colon carcinoma and epithelial cancers
- Evaluation of new or novel targets in developmental therapeutic approaches
- Development of new therapeutic strategies
- Gene signature analyses of therapeutic response
Investigators:
- Mohammad Aziz, Ph.D., Research Fellow
- Jennifer DeVecchio, Lead Technologist
- Tanvi Jani, Ph.D., Research Fellow
- Tapati Mazumdar, Ph.D., Research Fellow
- Kristi Peters, Ph.D., Research Associate
Collaborators
Investigators in the Department of Cancer Biology, LRI; the Department of Colorectal Surgery, DDI; the Taussig Cancer Institute, and the Case Comprehensive Cancer Center.
Brief Description:
We focus on (a) fundamental questions about how cell-surface death receptors of the tumor necrosis factor receptor superfamily and their signaling pathways function in inducing apoptosis and in the response of human solid tumors to chemotherapy in colorectal cancer; and (b) the role of specific genes in DNA damage-response mechanisms. We study the role of signaling via the Fas death receptor following DNA damage, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/cytolytic antibody/DR4-DR5 interactions, and synergistic interaction between death receptor- vs. drug-induced apoptosis or survival responses involved in drug resistance. We are elucidating how specific signaling pathways affect these responses, identifying new targets with potential therapeutic value, and engaging in drug discovery.
We have shown that 5-fluorouracil (FUra)/leucovorin (LV)-induced or thymidylate synthase-dependent cell death occurs via the Fas signaling pathway. Yet expression of the Fas cell-surface receptor is often downregulated in colorectal cancer. Fas can be upregulated following cell exposure to interferon-γ, which sensitizes these cells to FUra/LV-induced cell death in vitro and in xenograft models and can be further potentiated by agents aimed at TRAIL receptors. Other targets include survival signaling pathways (i.e., NF-κB, and PI3κ/Akt signaling pathways), hoping to improve therapeutic responses when agents targeting those pathways are combined with FUra/LV/IFN-γ, and/or agents against TRAIL receptors. Translational research efforts are ongoing, with the goal of improving therapeutic response and survival in colorectal cancer patients.
Selected References:
Carew JS, et al. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 2007;110:313-22.
Nawrocki ST, et al. Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. Cancer Res 2007;67:6987-94.
Phillips DC, et al. Ceramide-induced G(2) arrest in rhabdomyosarcoma (RMS) cells requires p21(Cip1/Waf1) induction and is prevented by MDM2 overexpression. Cell Death Differ 2007; 14:1780-91.
Phillips DC, et al. Sphingosine-induced apoptosis in rhabdomyosarcoma cell lines is dependent on pre-mitochondrial Bax activation and post-mitochondrial caspases. Cancer Res 2007;67:756-64.
Izeradjene K, Douglas L, Delaney A, Martin S, Houghton JA. Casein Kinase II (CK2) regulates FADD and caspase-8 recruitment to the death-inducing signaling complex (DISC) in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene 24:2050-2058, 2005.
Izeradjene K, Douglas L, Tillman DM, Delaney AB, Houghton JA. Reactive oxygen species regulate caspase activation in TRAIL-resistant human colon carcinoma cell lines. Cancer Res. 65:7436-7445, 2005.
Martin S, Phillips DC, Szekely-Szucs K, Elghazi L, Desmots F, Houghton JA. Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae. Cancer Res. 65:11447-58, 2005.
Turner PK, Houghton JA, Petak I, Tillman DM, Douglas L, Schwartzberg L, Billups C, Tan M, Panetta J, Stewart CF. Pharmacokinetics and pharmacodynamics of subcutaneous interferon gamma in patients receiving 5-fluorouracil and leucovorin. Cancer Chemother Pharmacol 53:253-260, 2004.
Geller JI, Szekely-Szucs K, Petak I, Doyle B, Houghton JA. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase (TS) inhibitors in colorectal carcinoma cells. Cancer Res 64:6296-6303, 2004.
Izeradjene K, Douglas L, Delaney A, Houghton JA. Casein kinase I (CKI) attenuates TRAIL-induced apoptosis by regulating the recruitment of FADD and procaspase-8 to the death inducing signaling complex. Cancer Res 64:8036-8044. 2004.
Izeradjene K, Douglas L, Delaney A, Houghton JA. Influence of Casein Kinase II (CK2) in TRAIL-induced apoptosis in human rhabdomyosarcoma cells. Clin Cancer Res 10:6650-6660, 2004.
Petak I, Danam RP, Tillman DM, Vernes R, Howell SR, Brent TP, Houghton JA. Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma Cell Death Diff 10:211-217, 2003.
Petak I, Vernes R, Szekely Szuks K, Anozie M, Izeradjene K, Douglas L, Tillman M, Houghton JA. A caspase-8-independent component in TRAIL/APO2L-induced cell death in human rhabdomyosarcoma cells. Cell Death Diff 10:729-39, 2003.
Tillman DM, Izeradjene K, Szekely Szucs K, Douglas L and Houghton JA. Rottlerin sensitizes colon carcinoma cells to TRAIL-induced apoptosis via uncoupling of the mitochondria independent of PKC. Cancer Res 63:5118-5125, 2003.
Geller J, Petak I, Szekely Szucs K, Nagy K, Tillman DM, Houghton JA. Interferon-γ-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the IAP survivin. Clin Cancer Res 9:6504-6515, 2003.
Schwartzberg L, Petak I, Stewart C, Turner PK, Ashley J, Tillman DM, Douglas L, Mihalik R, Weir A, Tauer K, Shope S, Houghton JA. Modulation of the Fas signaling pathway by interferon-γ in therapy of colon cancer: Phase I trial and correlative studies of interferon-γ, 5-fluorouracil and leucovorin. Clin Cancer Res 8:2488-2498, 2002.
Totth A, Sebestyen A, Barna G, Nagy K, Gondor A, Bocsi J, Mihalik R, Petak I, Houghton J, Kopper L. TGF beta 1 induces caspase-dependent but death-receptor independent apoptosis in lymphoid cells. Anticancer Res 21:1207-12, 2001.
Hwang H-S, Davis TW, Houghton JA, Kinsella TJ. Radiosensitivty of thymidylate synthase-deficient human tumor cells is affected by progression through the G1 restriction point into S-phase: Impliactions for fluoropyrimidine (FP) radiosensitization (RS). Cancer Res 60:92-100, 2000.
Harwood FG, Kasibhatla S, Petak I, Vernes R, Green DR, Houghton JA. Regulation of FasL by NF-κB and AP-1 in Fas-dependent thymineless death of colon carcinoma cells. J Biol Chem, 275:10023-10029, 2000.
Petak I, Tillman DM, Harwood FG, Houghton JA. Fas -dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 60:2643-2650, 2000.
Petak I, Douglas L, Tillman DM, Vernes R, Houghton JA. Rhabdomyosarcoma cell lines are resistant to Fas- and highly sensitive to TRAIL-induced apoptosis. Clin Cancer Res 6:4119-4127, 2000.
Petak I, Tillman DM, Houghton JA. P53-dependence of Fas induction amd acute apoptosis in response to 5-fluorouracil-leucovorin in human colon carcinoma cell lines. Clin Cancer Res 6:4432-4441, 2000.
Tillman DM, Petak I, Houghton JA. A Fas-dependent component in 5-fluorouracil/leucovorin-induced cytotoxicity in colon carcinoma cells. Clin Cancer Res 5:425-430, 1999.
Tillman DM, Harwood FG, Gibson AA, Houghton JA. Expression of genes that regulate Fas signaling and Fas-mediated apoptosis in colon carcinoma cells. Cell Death Diff. 5:450-457, 1998.
Houghton JA, Harwood FG, Tillman DM. Thymineless death in colon carcinoma cells is mediated via Fas signaling. Proc. Natl. Acad. Sci. USA 94:8144-8149, 1997.
Houghton JA, Harwood FG, Gibson AA, Tillman DM. The Fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res 3:2205-2209, 1997.