Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway
- Authors
- Lee, S-H; Jung, Y-S; Chung, J-Y; Oh, A. Y.; Lee, S-J; Choi, D. H.; Jang, S. M.; Jang, K-S; Paik, S. S.; Ha, N-C; Park, B-J
- Issue Date
- Dec-2011
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- DPC4/Smad4; colon cancer; PUMA; PAK1
- Citation
- CELL DEATH & DISEASE, v.2, pp.1 - 11
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL DEATH & DISEASE
- Volume
- 2
- Start Page
- 1
- End Page
- 11
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/166982
- DOI
- 10.1038/cddis.2011.116
- ISSN
- 2041-4889
- Abstract
- DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-beta signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-beta can contribute to cancer progression through transcriptional target genes, such as Snail, MMPs, and epithelial-mesenchymal transition (EMT)-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-beta signaling-independent advantage, which should be essential for cancer cell survival. Here, we provide the evidences about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4-deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that Siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 renders the resistance to serum-deprivation-induced cell death, which is the TGF-beta-independent tumor suppressive role of Smad4.
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