NSAID-Induced Apoptosis in Rous Sarcoma Virus-Transformed Chicken Embryo Fibroblasts is Dependent on v-src and c-myc and is Inhibited by bcl-2

Lu, Xiaojun; Fairbairn, Daryl W.; Bradshaw, William S.; O’Neill, Kim L.; Ewert, Donald L.; Simmons, Denise R.

doi:10.1016/s0090-6980(97)00125-1

Cited by 22 publications

(14 citation statements)

References 33 publications

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“…Apoptosis induced by NSAIDs was previously demonstrated in chicken embryo fibroblasts when treated with any one of 17 different COX inhibitors (7). This apoptotic response was accompanied by the generation of nucleosome-sized ladders of DNA fragments in treated cells and other apoptosis-associated biochemical events, such as induction of tissue transglutaminase and inhibition by bcl-2 (7,11). COX-2 mRNA and protein were also induced by apoptotic NSAIDs, similar to these studies (7,11).…”

Section: Discussionsupporting

confidence: 76%

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

Simmons

Botting

Robertson

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

139

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The transformed monocyte͞macrophage cell line J774.2 undergoes apoptosis when treated for 48 h with competitive inhibitors of cyclooxygenase (COX) isoenzymes 1 and 2. Many of these nonsteroid antiinf lammatory drugs (NSAIDs), but in particular diclofenac, induce during this time period a COX activity that coincides with a robust induction of COX-2 protein. Induction of this activity requires high, apoptosis-inducing concentrations of diclofenac (>100 M). Prolonged treatment of J774.2 cells with lower doses of diclofenac inhibits COX activity, indicating that diclofenac is a time-dependent, pseudoirreversible inhibitor of COX-2. It is difficult to wash out the inhibition. However, the activity evoked by high concentrations of diclofenac has a profoundly distinct COX active site that allows diclofenac, its inducer, to be washed readily from its active site. The diclofenac-induced activity also has the unusual property of being more sensitive to inhibition by acetaminophen (IC 50 ‫؍‬ 0.1-1.0 mM) than COX-2 induced with bacterial lipopolysaccharide. Moreover, relative to COX-1 or COX-2, diclofenac-induced enzyme activity shows significantly reduced sensitivity to inhibition by diclofenac or other competitively acting nonsteroid antiinf lammatory drugs (NSAIDs) and the enzyme activity is insensitive to aspirin. If the robust induction of COX-2 observed is responsible for diclofenac-induced COX enzyme activity, it is clear that COX-2 can, therefore, exist in two catalytically active states. A luciferase reporter-construct that contains part of the COX-2 structure and binds into the membrane showed that chronic diclofenac treatment of fibroblasts results in marked mobilization of the fusion protein. Such a mobilization could result in enzymatically distinct COX-2 populations in response to chronic diclofenac treatment.The cloning of cyclooxygenase-2 (COX-2) in 1991 (1-3) explained many long-standing anomalies relating to the previous assumption of a single COX enzyme. However, not all of the problems have been solved by the characterization of two COX enzymes originating from different genes. One such problem is the effect of acetaminophen, which, unlike nonsteroid antiinflammatory drugs (NSAIDs), produces analgesia and antipyresis but has little effect on inflammation. The existence of additional COX enzymes was therefore postulated (4).Acetaminophen is a weak inhibitor of COX-1 and COX-2, which displays some selectivity toward COX enzymes from different organs. Thus, it is a more potent inhibitor of COX from dog and rabbit brain than that of dog spleen (4). The activity of acetaminophen in vitro also depends on the addition of cofactors. In the presence of glutathione and hydroquinone, acetaminophen inhibited COX activity of bull seminal vesicle microsomes but, in the absence of these cofactors, stimulated that of bovine and ram seminal vesicle microsomes (5). After the recognition of COX-1 and COX-2, by using cultured whole cells, acetaminophen demonstrated a low inhibitory potency for COX enzymes. Only IC 3...

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Section: Discussionsupporting

confidence: 76%

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

Simmons

Botting

Robertson

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

139

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“…The results reported here, in conjunction with these earlier studies, suggest that oncoproteins, such as Src, Ras, and Abl, which regulate cytoplasmic signaling pathways, have both proand antiapoptotic effects and that the balance between the proapoptotic and antiapoptotic signals generated by these oncoproteins determines whether transformation or apoptosis occurs. The generation of a proapoptotic signal by v-Src may explain the sensitivity of v-src-transformed cells to apoptosis induced by various drug treatments (15,44).…”

Section: Discussionmentioning

confidence: 99%

v-Src Generates a p53-Independent Apoptotic Signal

Webb

Jimenez

Martin

2000

Molecular and Cellular Biology

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Evasion of apoptosis appears to be a necessary event in tumor progression. Some oncogenes, such as c-myc and E1A, induce apoptosis in the absence of survival factors. However, others, such as bcl-2 and v-src, activate antiapoptotic pathways. For v-Src, these antiapoptotic pathways are dependent on the function of Ras, phosphatidylinositol (PI) 3-kinase, and Stat3. Here we asked whether v-Src can activate a proapoptotic signal when survival signaling is inhibited. We show that when the functions of Ras and PI 3-kinase are inhibited, v-src-transformed Rat-2 fibroblasts undergo apoptosis, evidenced by loss of adherence, nuclear fragmentation, and chromosomal DNA degradation. The apoptotic response is dependent on activation of caspase 3. Under similar conditions nontransformed Rat-2 cells undergo considerably lower levels of apoptosis. Apoptosis induced by v-Src is accompanied by a loss of mitochondrial membrane potential and release of cytochrome c and is blocked by overexpression of bcl-2, indicating that it is mediated by the mitochondrial pathway. However apoptosis induced by v-Src is not accompanied by an increase in the level of p53 and is not dependent on p53 function. Thus v-Src generates a p53-independent proapoptotic signal.

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“…However, a thorough literature search revealed several studies reporting an induction of COX-2 expression by COX inhibitors ( 48,(53)(54)(55)(56)(57)(58)(59), including celecoxib ( 37,38,60 ). Furthermore, celecoxib was shown to enhance PGE 2 release from hematopoietic cancer cells at a concentration of 40 µM, but to exert inhibitory effects at 10 µM ( 61 ).…”

Section: Impact Of Exogenous Pgs On Nuclear and Total Levels Of Ppar ␥mentioning

confidence: 99%

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

Ramer

Walther

Borchert

et al. 2013

Journal of Lipid Research

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NSAID-Induced Apoptosis in Rous Sarcoma Virus-Transformed Chicken Embryo Fibroblasts is Dependent on v-src and c-myc and is Inhibited by bcl-2

Cited by 22 publications

References 33 publications

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs

v-Src Generates a p53-Independent Apoptotic Signal

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

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