Apoptosis suppression by candidate oncogene PLAC8 is reversed in other cell types

TY - JOUR

T1 - Apoptosis suppression by candidate oncogene PLAC8 is reversed in other cell types

AU - Mourtada-Maarabouni, Mirna

AU - Watson, David

AU - Munir, Mamoona

AU - Farzaneh, Farzin

AU - Williams, Gwyn T

PY - 2013/1

Y1 - 2013/1

N2 - 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.

AB - 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.

KW - Alternative Splicing

KW - Apoptosis

KW - Breast Neoplasms

KW - Cell Line, Transformed

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cells, Cultured

KW - Down-Regulation

KW - Female

KW - Humans

KW - Leukemia

KW - Male

KW - Neoplasm Proteins

KW - Pancreatic Neoplasms

KW - Proteins

KW - RNA Interference

KW - RNA, Messenger

KW - RNA, Small Interfering

KW - Recombinant Proteins

KW - T-Lymphocytes

KW - Up-Regulation

U2 - 10.2174/1568009611309010080

DO - 10.2174/1568009611309010080

M3 - Article

C2 - 22920440

SN - 1568-0096

VL - 13

SP - 80

EP - 91

JO - CURRENT CANCER DRUG TARGETS

JF - CURRENT CANCER DRUG TARGETS

IS - 1

M1 - N/A

ER -