Abstract:
:Targets for cancer therapy are conventionally selected by identification of molecules acting downstream of established tumour suppressors and oncoproteins, such as p53, c-Myc and Ras. However, the forward genetics approach provides an alternative, conceptually distinct, strategy for identifying target molecules de novo. This approach, which uses unbiased selection protocols relying directly on the effects of the genes themselves on cell fate, has the potential to identify novel cancer targets which have not been highlighted by conventional approaches. PLAC8, a small cysteine-rich protein with little homology to other proteins, has been identified by both these strategies. Here we confirm that PLAC8 overexpression protects some cancer cell lines from apoptosis, but we also demonstrate for the first time that, in other cell lines, the effect of PLAC8 overexpression is reversed, and, in this context, PLAC8 induces apoptosis. In both cases siRNA-mediated down-regulation of PLAC8 confirms that the activity of endogenously expressed PLAC8 is consistent with that shown by exogenous PLAC8. The striking reversal of the effects of PLAC8 in different cell types is not readily explained by the level of PLAC8 expressed within the cells, by the differential expression of PLAC8 splice variants observed, or by the p53 status of the host cells. This intriguing contrast in the effects of PLAC8 on cell fate in different cellular contexts presents attractive possibilities for the development of novel therapies for cancers, such as pancreatic cancers, where PLAC8 has been shown to be overexpressed.
journal_name
Curr Cancer Drug Targetsjournal_title
Current cancer drug targetsauthors
Mourtada-Maarabouni M,Watson D,Munir M,Farzaneh F,Williams GTsubject
Has Abstractpub_date
2013-01-01 00:00:00pages
80-91issue
1eissn
1568-0096issn
1873-5576pii
CCDT-EPUB-20120816-4journal_volume
13pub_type
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journal_title:Current cancer drug targets
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