Premium
Development of a small anti‐cancer molecule targeting both the intrinsic and extrinsic pathways of apoptosis
Author(s) -
Titorenko Vladimir,
Goldberg Alexander,
Beach Adam
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.797.1
Subject(s) - apoptosis , programmed cell death , mitochondrion , microbiology and biotechnology , cancer cell , biology , cancer , caspase , cell culture , cancer research , chemistry , biochemistry , genetics
Our chemical genetic screen for small molecules that increase lifespan in yeast cellular models of aging by targeting mitochondria‐controlled apoptosis identified lithocholic acid (LCA) as one of such molecules. Aging is one of the major risk factors of cancer, an age‐related disease whose onset can be delayed and incidence reduced by certain pharmacological antiaging interventions. We therefore sought to examine if LCA exhibits an anti‐tumor effect in cultured human cancer cells by activating certain anti‐cancer processes that may play an essential role in cellular aging. We found that LCA, at concentrations that are not cytotoxic to primary cultures of human neurons, kills the neuroblastoma (NB) cell lines BE(2)‐m17, SK‐n‐SH, SK‐n‐ MCIXC and Lan‐1. In the case of BE(2)‐m17, SK‐n‐SH and SK‐n‐ MCIXC cells, the LCA anti‐tumor effect is due to apoptotic cell death. In contrast, the LCA‐triggered death of Lan‐1 cells is not caused by apoptosis. Our findings imply that LCA kills BE(2)‐m17 and SK‐n‐MCIXC cell lines by triggering not only the intrinsic (mitochondrial) apoptotic cell death pathway driven by mitochondrial outer membrane permeabilization and initiator caspase‐9 activation, but also the extrinsic (death receptor) pathway of apoptosis involving activation of the initiator caspase‐ 8. Our data suggest a molecular mechanism underlying a potent and selective anti‐tumor effect of LCA in cultured human NB cells. Importantly, we found that a similar mechanism underlies a broad anti‐tumor effect of LCA in cultured mammalian cancer cells derived from different tissues and organisms. Supported by NSERC of Canada.