The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists
Open accessAbstract
The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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Cites
Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis
Thayer, S. P., di Magliano, M. P., Heiser, P. W., Nielsen, C. M., Roberts, D. J., Lauwers, G. Y., Qi, Y. P., Gysin, S., Castillo, C. F.-D., Yajnik, V., et al. (2003) · Nature · doi:10.1038/nature02009 · Cited by 1,480
Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine
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Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours
Berman, D. M., Karhadkar, S. S., Maitra, A., Montes de Oca, R., Gerstenblith, M. R., Briggs, K., Parker, A. R., Shimada, Y., Eshleman, J. R., Watkins, D. N., et al. (2003) · Nature · doi:10.1038/nature01972 · Cited by 1,251
Tissue repair and stem cell renewal in carcinogenesis
Beachy, P. A., Karhadkar, S. S., & Berman, D. M. (2004) · Nature · doi:10.1038/nature03100 · Cited by 1,208
Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer
Watkins, D. N., Berman, D. M., Burkholder, S. G., Wang, B., Beachy, P. A., & Baylin, S. B. (2003) · Nature · doi:10.1038/nature01493 · Cited by 1,082
Small molecule modulation of Smoothened activity
Chen, J. K., Taipale, J., Young, K. E., Maiti, T., & Beachy, P. A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182542899 · Cited by 992
Hedgehog signalling in prostate regeneration, neoplasia and metastasis
Karhadkar, S. S., Steven Bova, G., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., Isaacs, J. T., Berman, D. M., & Beachy, P. A. (2004) · Nature · doi:10.1038/nature02962 · Cited by 950
Haycraft, C. J., Banizs, B., Aydin-Son, Y., Zhang, Q., Michaud, E. J., & Yoder, B. K. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010053 · Cited by 902
Mutations in SUFU predispose to medulloblastoma
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Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade
Berman, D. M., Karhadkar, S. S., Hallahan, A. R., Pritchard, J. I., Eberhart, C. G., Watkins, D. N., Chen, J. K., Cooper, M. K., Taipale, J., Olson, J. M., et al. (2002) · Science · doi:10.1126/science.1073733 · Cited by 803
Cited by
Targeting cancer stem cell pathways for cancer therapy
Yang, L., Shi, P., Zhao, G., Xu, J., Peng, W., Zhang, J., Zhang, G., Wang, X., Dong, Z., Chen, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0110-5 · Cited by 1,906
G protein-coupled receptors: novel targets for drug discovery in cancer
Lappano, R., & Maggiolini, M. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3320 · Cited by 717
KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma
Morris, J. P., Wang, S. C., & Hebrok, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2899 · Cited by 567
A highlight on Sonic hedgehog pathway
Carballo, G. B., Honorato, J. R., de Lopes, G. P. F., & Spohr, T. C. L. D. S. E. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0220-7 · Cited by 460
The Hedgehog's tale: developing strategies for targeting cancer
Ng, J. M. Y., & Curran, T. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3079 · Cited by 398
Metadata
- Authors
- Lauth, M., Bergström, Å., Shimokawa, T., & Toftgård, R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2007-05-15
- Volume
- 104
- Issue
- 20
- Pages
- 8455-8460
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2110321605
- Cited by
- 782
- References
- 36
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Open access
- green
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