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Published on: July 29, 2010
SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss
Xinqi Xi1, Ling Liu1, Natasha Tuano2
1Department of Biochemistry and Molecular Biology and Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Abstract:
Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli (APC) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRP19 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRP19 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19. Moreover, we show that SRP19 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRP19 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.
Insights
Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor gene creates a vulnerability in colorectal cancers. Targeting SRP19 with low-dose arsenic trioxide inhibits cancer cell proliferation by inducing ER-stress.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Loss of the Adenomatous Polyposis Coli (APC) tumor suppressor gene is a key event in colorectal cancer development.
- Targeting tumor suppressor genes directly is not currently feasible, leaving patients with APC-deficient tumors without treatment options.
Purpose of the Study:
- To identify a unique vulnerability in colorectal cancers with heterozygous APC loss.
- To explore therapeutic strategies targeting this vulnerability.
Main Methods:
- Investigated the role of SRP19, located near APC, in cancers with APC loss.
- Assessed the impact of heterozygous APC/SRP19 loss on SRP19 levels and protein secretion.
- Examined the effect of low-dose arsenic trioxide on SRP19-deficient cells and animal models.
Main Results:
- Heterozygous loss of APC and SRP19 leads to reduced SRP19 expression.
- SRP19 is rate-limiting for Signal Recognition Particle formation, impacting protein secretion and increasing ER-stress.
- Low-dose arsenic trioxide effectively inhibits proliferation in cell lines and animal models with APC/SRP19 loss.
Conclusions:
- Identified SRP19 and the protein secretion pathway as a vulnerability in APC-deficient colorectal cancers.
- Demonstrated that low-dose arsenic trioxide can be a therapeutic strategy for these cancers.
- Provided a framework for identifying and translating vulnerabilities associated with tumor suppressor gene loss.
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