12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase

Mark Garzotto, Margaret White-Jones, Youwei Jiang, Desiree Ehleiter, Wen Chieh Liao, Adriana Haimovitz-Friedman, Zvi Fuks, Richard Kolesnick

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Protein kinase C (PKC) activation is often antiapoptotic, although in a few cell types PKC initiates apoptosis by an unknown mechanism. Recent investigations showed that activation of PKCα by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) induced apoptosis in LNCaP prostate cancer cells. The present studies examine the mechanism of this effect and show that de novo ceramide generation through the enzyme ceramide synthase is required. TPA induced rapid ceramide generation, which was detectable by 1 h and increased linearly for 12 h. TPA-induced apoptosis was measurable by 12 h and was progressive for 48 h. Investigations into the mechanism of TPA-induced ceramide generation revealed that acid and neutral sphingomyelinase activities were not enhanced. However, TPA induced an increase in ceramide synthase activity that persisted for at least 16 h. Treatment with fumonisin B1, a specific natural inhibitor of ceramide synthase, abrogated both ceramide production and TPA-induced apoptosis. Ceramide analogues bypassed fumonisin B1 inhibition to initiate apoptosis directly. Thus, ceramide appears to be a necessary signal for TPA-induced apoptosis in LNCaP cells. This represents the first description of a pathway by which PKC may signal apoptosis.

Original languageEnglish (US)
Pages (from-to)2260-2264
Number of pages5
JournalCancer Research
Volume58
Issue number10
StatePublished - May 15 1998
Externally publishedYes

Fingerprint

Tetradecanoylphorbol Acetate
Ceramides
Apoptosis
Protein Kinase C
Sphingomyelin Phosphodiesterase
dihydroceramide desaturase
Prostatic Neoplasms
Acids
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Garzotto, M., White-Jones, M., Jiang, Y., Ehleiter, D., Liao, W. C., Haimovitz-Friedman, A., ... Kolesnick, R. (1998). 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Research, 58(10), 2260-2264.

12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. / Garzotto, Mark; White-Jones, Margaret; Jiang, Youwei; Ehleiter, Desiree; Liao, Wen Chieh; Haimovitz-Friedman, Adriana; Fuks, Zvi; Kolesnick, Richard.

In: Cancer Research, Vol. 58, No. 10, 15.05.1998, p. 2260-2264.

Research output: Contribution to journalArticle

Garzotto, M, White-Jones, M, Jiang, Y, Ehleiter, D, Liao, WC, Haimovitz-Friedman, A, Fuks, Z & Kolesnick, R 1998, '12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase', Cancer Research, vol. 58, no. 10, pp. 2260-2264.
Garzotto M, White-Jones M, Jiang Y, Ehleiter D, Liao WC, Haimovitz-Friedman A et al. 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. Cancer Research. 1998 May 15;58(10):2260-2264.
Garzotto, Mark ; White-Jones, Margaret ; Jiang, Youwei ; Ehleiter, Desiree ; Liao, Wen Chieh ; Haimovitz-Friedman, Adriana ; Fuks, Zvi ; Kolesnick, Richard. / 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase. In: Cancer Research. 1998 ; Vol. 58, No. 10. pp. 2260-2264.
@article{01b4bd7ae73245ba9391ab93f536e50a,
title = "12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase",
abstract = "Protein kinase C (PKC) activation is often antiapoptotic, although in a few cell types PKC initiates apoptosis by an unknown mechanism. Recent investigations showed that activation of PKCα by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) induced apoptosis in LNCaP prostate cancer cells. The present studies examine the mechanism of this effect and show that de novo ceramide generation through the enzyme ceramide synthase is required. TPA induced rapid ceramide generation, which was detectable by 1 h and increased linearly for 12 h. TPA-induced apoptosis was measurable by 12 h and was progressive for 48 h. Investigations into the mechanism of TPA-induced ceramide generation revealed that acid and neutral sphingomyelinase activities were not enhanced. However, TPA induced an increase in ceramide synthase activity that persisted for at least 16 h. Treatment with fumonisin B1, a specific natural inhibitor of ceramide synthase, abrogated both ceramide production and TPA-induced apoptosis. Ceramide analogues bypassed fumonisin B1 inhibition to initiate apoptosis directly. Thus, ceramide appears to be a necessary signal for TPA-induced apoptosis in LNCaP cells. This represents the first description of a pathway by which PKC may signal apoptosis.",
author = "Mark Garzotto and Margaret White-Jones and Youwei Jiang and Desiree Ehleiter and Liao, {Wen Chieh} and Adriana Haimovitz-Friedman and Zvi Fuks and Richard Kolesnick",
year = "1998",
month = "5",
day = "15",
language = "English (US)",
volume = "58",
pages = "2260--2264",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - 12-O-tetradecanoylphorbol-13-acetate-induced apoptosis in LNCaP cells is mediated through ceramide synthase

AU - Garzotto, Mark

AU - White-Jones, Margaret

AU - Jiang, Youwei

AU - Ehleiter, Desiree

AU - Liao, Wen Chieh

AU - Haimovitz-Friedman, Adriana

AU - Fuks, Zvi

AU - Kolesnick, Richard

PY - 1998/5/15

Y1 - 1998/5/15

N2 - Protein kinase C (PKC) activation is often antiapoptotic, although in a few cell types PKC initiates apoptosis by an unknown mechanism. Recent investigations showed that activation of PKCα by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) induced apoptosis in LNCaP prostate cancer cells. The present studies examine the mechanism of this effect and show that de novo ceramide generation through the enzyme ceramide synthase is required. TPA induced rapid ceramide generation, which was detectable by 1 h and increased linearly for 12 h. TPA-induced apoptosis was measurable by 12 h and was progressive for 48 h. Investigations into the mechanism of TPA-induced ceramide generation revealed that acid and neutral sphingomyelinase activities were not enhanced. However, TPA induced an increase in ceramide synthase activity that persisted for at least 16 h. Treatment with fumonisin B1, a specific natural inhibitor of ceramide synthase, abrogated both ceramide production and TPA-induced apoptosis. Ceramide analogues bypassed fumonisin B1 inhibition to initiate apoptosis directly. Thus, ceramide appears to be a necessary signal for TPA-induced apoptosis in LNCaP cells. This represents the first description of a pathway by which PKC may signal apoptosis.

AB - Protein kinase C (PKC) activation is often antiapoptotic, although in a few cell types PKC initiates apoptosis by an unknown mechanism. Recent investigations showed that activation of PKCα by 12-O-tetradecanoyl-phorbol 13-acetate (TPA) induced apoptosis in LNCaP prostate cancer cells. The present studies examine the mechanism of this effect and show that de novo ceramide generation through the enzyme ceramide synthase is required. TPA induced rapid ceramide generation, which was detectable by 1 h and increased linearly for 12 h. TPA-induced apoptosis was measurable by 12 h and was progressive for 48 h. Investigations into the mechanism of TPA-induced ceramide generation revealed that acid and neutral sphingomyelinase activities were not enhanced. However, TPA induced an increase in ceramide synthase activity that persisted for at least 16 h. Treatment with fumonisin B1, a specific natural inhibitor of ceramide synthase, abrogated both ceramide production and TPA-induced apoptosis. Ceramide analogues bypassed fumonisin B1 inhibition to initiate apoptosis directly. Thus, ceramide appears to be a necessary signal for TPA-induced apoptosis in LNCaP cells. This represents the first description of a pathway by which PKC may signal apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=0032523941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032523941&partnerID=8YFLogxK

M3 - Article

VL - 58

SP - 2260

EP - 2264

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 10

ER -