Premium
Ceramide plays a prominent role in MDA‐7/IL‐24‐induced cancer‐specific apoptosis
Author(s) -
Sauane Moira,
Su Zaozhong,
Dash Rupesh,
Liu Xiang,
Norris James S.,
Sarkar Devanand,
Lee SeokGeun,
Allegood Jeremy C.,
Dent Paul,
Spiegel Sarah,
Fisher Paul B.
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21969
Subject(s) - ceramide , ceramide synthase , acid sphingomyelinase , apoptosis , sphingomyelin , sphingomyelin phosphodiesterase , biology , endoplasmic reticulum , microbiology and biotechnology , cancer cell , programmed cell death , lipid signaling , unfolded protein response , biochemistry , cancer , enzyme , genetics , membrane
Melanoma differentiation associated gene‐7/interleukin‐24 ( mda ‐7/IL‐24) uniquely displays broad cancer‐specific apoptosis‐inducing activity through induction of endoplasmic reticulum (ER) stress. We hypothesize that ceramide, a promoter of apoptosis, might contribute to mda ‐7/IL‐24 induction of apoptosis. Ad. mda ‐7‐infected tumor cells, but not normal cells, showed increased ceramide accumulation. Infection with Ad. mda ‐7 induced a marked increase in various ceramides (C16, C24, C24:1) selectively in prostate cancer cells. Inhibiting the enzyme serine palmitoyltransferase (SPT) using the potent SPT inhibitor myriocin (ISP1), impaired mda ‐7/IL‐24‐induced apoptosis and ceramide production, suggesting that ceramide formation caused by Ad. mda ‐7 occurs through de novo synthesis of ceramide and that ceramide is required for mda ‐7/IL‐24‐induced cell death. Fumonisin B1 (FB1) elevated ceramide formation as well as apoptosis induced by Ad. mda ‐7, suggesting that ceramide formation may also occur through the salvage pathway. Additionally, Ad. mda ‐7 infection enhanced expression of acid sphingomyelinase (ASMase) with a concomitant increase in ASMase activity and decreased sphingomyelin in cancer cells. ASMase silencing by RNA interference inhibited the decreased cell viability and ceramide formation after Ad. mda ‐7 infection. Ad. mda ‐7 activated protein phosphatase 2A (PP2A) and promoted dephosphorylation of the anti‐apoptotic molecule BCL‐2, a downstream ceramide‐mediated pathway of mda ‐7/IL‐24 action. Pretreatment of cells with FB1 or ISP‐1 abolished the induction of ER stress markers (BiP/GRP78, GADD153 and pospho‐eIF2α) triggered by Ad. mda ‐7 infection indicating that ceramide mediates ER stress induction by Ad. mda ‐7. Additionally, recombinant MDA‐7/IL‐24 protein induced cancer‐specific production of ceramide. These studies define ceramide as a key mediator of an ER stress pathway that may underlie mda ‐7/IL‐24 induction of cancer‐specific killing. J. Cell. Physiol. 222: 546–555, 2010. © 2009 Wiley‐Liss, Inc.