期刊
CANCERS
卷 11, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/cancers11050693
关键词
colorectal cancer; protein kinase C alpha; Wnt/beta-catenin; tumor suppressor; drug target
类别
资金
- Ligue Regionale contre le Cancer (Languedoc-Roussillon committee)
- Fondation ARC pour la Recherche sur le Cancer [3636]
- Region Languedoc-Roussillon (Chercheur d'Avenir committee)
- GEFLUC (Languedoc-Roussillon committee)
- Lilly France
- Ligue Nationale contre le Cancer
- Fondation ARC pour la Recherche sur le Cancer
Inactivating mutations of the tumor suppressor Adenomatosis Polyposis Coli (APC), which are found in familial adenomatosis polyposis and in 80% of sporadic colorectal cancers (CRC), result in constitutive activation of the Wnt/beta-catenin pathway and tumor development in the intestine. These mutations disconnect the Wnt/beta-catenin pathway from its Wnt extracellular signal by inactivating the APC/GSK3-beta/axin destruction complex of beta-catenin. This results in sustained nuclear accumulation of beta-catenin, followed by beta-catenin-dependent co-transcriptional activation of Wnt/beta-catenin target genes. Thus, mechanisms acting downstream of APC, such as those controlling beta-catenin stability and/or co-transcriptional activity, are attractive targets for CRC treatment. Protein Kinase C-alpha (PKC alpha) phosphorylates the orphan receptor ROR alpha that then inhibits beta-catenin co-transcriptional activity. PKCa also phosphorylates beta-catenin, leading to its degradation by the proteasome. Here, using both in vitro (DLD-1 cells) and in vivo (C57BL/6J mice) PKC alpha knock-in models, we investigated whether enhancing PKC alpha function could be beneficial in CRC treatment. We found that PKC alpha is infrequently mutated in CRC samples, and that inducing PKC alpha function is not deleterious for the normal intestinal epithelium. Conversely, di-terpene ester-induced PKC alpha activity triggers CRC cell death. Together, these data indicate that PKC alpha is a relevant drug target for CRC treatment.
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