Sj. Chi et al., Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells, ONCOGENE, 18(13), 1999, pp. 2281-2290
To prevent neoplasia, cells of multicellular organisms activate cellular di
sposal programs such as apoptosis in response to deregulated oncogene expre
ssion, making the suppression of such programs an essential step for potent
ially neoplastic cells to become established as clinically relevant tumors.
Since the mutation of ras proto-oncogenes, the most frequently mutated pro
tooncogenes in human tumors, is very rare in some tumor types such as gliob
lastomas and gastric cancers, we hypothesized that mutated ras genes might
activate a cell death program that cannot be overcome by these tumor types.
Here we show that the expression of oncogenically mutated ras gene induces
cellular degeneration accompanied by cytoplasmic vacuoles in human glioma
and gastric cancer cell lines. Cells dying as a result of oncogenic Ras exp
ression had relatively well-preserved nuclei that were negative for TUNEL s
taining. An immunocytochemical analysis demonstrated that the cytoplasmic v
acuoles are derived mainly from lysosomes, This oncogenic Ras-induced cell
death occurred in the absence of caspase activation, and was not inhibited
by the overexpression of anti-apoptotic Bcl-2 protein. These observations s
uggested that oncogenic Ras-induced cell death is most consistent with a ty
pe of programmed cell death designated 'type 2 physiological cell death' or
'autophagic degeneration', and that this cell death is regulated by a mole
cular mechanism distinct from that of apoptosis, Our findings suggest a pos
sible role for this non-apoptotic cell death in the prevention of neoplasia
, and the activation of the non-apoptotic cell death program may become a p
otential cancer therapy complementing apoptosis-based therapies. In additio
n, the approach used in this study may be a valuable way to find geneticall
y-regulated cell suicide programs that cannot be overcome by particular tum
or types.