Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II)

Kazuto Nishio, Yoshikazu Sugimoto, Yasuhiro Fujiwara, Tohru Ohmori, Toshihiko Morikage, Yuichiro Takeda, Masahiro Ohata, Nagahiro Saijo

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

We have investigated the effect of cis-diamminedichloroplatinum(II) (CDDP) on signal transduction pathways. CDDP treatment did not cause any change in the binding of [3H]phorbol dibutyrate to PC-9 (human lung adenocarcinoma cell line) cells, a measure of protein kinase C activation. However, 2-h CDDP treatment (20 μg/ml) caused ∼ 200% increase in 1,2-sn-diacylglycerol (DAG) production and ∼ 50% decrease in inositol 1,4,5-triphosphate production. To explore the different source of DAG, we analyzed phospholipids labeled with [14C]choline by TLC and revealed that [14C]choline-labeled phosphatidylcholine (PC) was decreased to 50% by CDDP treatment. This suggested that PC turnover was increased by CDDP-treatment. PC-specific phospholipase C (PC-PLC) activity was increased to 2.5-fold (2.58±0.28 nmol/mg protein per min) by 2 h CDDP (20 μg/ml) treatment compared with control (1.05±0.24 nmol/mg protein per min). Treatment of CDDP also stimulated PC-PLC in the crude membrane extract from PC-9 cells. CDDP had no effect on the activities of phospholipase A2 and D. Trans-DDP, which has far less cytotoxicity than its stereoisomer, CDDP, did not cause any change in PC-PLC activity. A significant inhibition of DNA synthesis (< 80%) occurred 4 h after 2 h CDDP (20 μg/ml) treatment. These results demonstrated that CDDP-induced PC-PLC activation was an early event in CDDP-induced cytotoxicity and suggested that the effects of CDDP on signal transduction pathways had an important role in CDDP-induced cytotoxicity.

Original languageEnglish
Pages (from-to)1622-1628
Number of pages7
JournalJournal of Clinical Investigation
Volume89
Issue number5
Publication statusPublished - 1992
Externally publishedYes

Fingerprint

Type C Phospholipases
Phosphatidylcholines
Cisplatin
Hydrolysis
Choline
Signal Transduction
Phospholipase D
Stereoisomerism
Inositol 1,4,5-Trisphosphate
Phospholipases A2
Diglycerides
Complex Mixtures
Protein Kinase C
Phospholipids
Proteins
Cell Line
Membranes
DNA

Keywords

  • cis-diam-minedichloroplatinum(II)
  • Phosphatidylcholine
  • Phospholipase C

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nishio, K., Sugimoto, Y., Fujiwara, Y., Ohmori, T., Morikage, T., Takeda, Y., ... Saijo, N. (1992). Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II). Journal of Clinical Investigation, 89(5), 1622-1628.

Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II). / Nishio, Kazuto; Sugimoto, Yoshikazu; Fujiwara, Yasuhiro; Ohmori, Tohru; Morikage, Toshihiko; Takeda, Yuichiro; Ohata, Masahiro; Saijo, Nagahiro.

In: Journal of Clinical Investigation, Vol. 89, No. 5, 1992, p. 1622-1628.

Research output: Contribution to journalArticle

Nishio, K, Sugimoto, Y, Fujiwara, Y, Ohmori, T, Morikage, T, Takeda, Y, Ohata, M & Saijo, N 1992, 'Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II)', Journal of Clinical Investigation, vol. 89, no. 5, pp. 1622-1628.
Nishio, Kazuto ; Sugimoto, Yoshikazu ; Fujiwara, Yasuhiro ; Ohmori, Tohru ; Morikage, Toshihiko ; Takeda, Yuichiro ; Ohata, Masahiro ; Saijo, Nagahiro. / Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II). In: Journal of Clinical Investigation. 1992 ; Vol. 89, No. 5. pp. 1622-1628.
@article{8029e195761f4f778da9a01444a72400,
title = "Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II)",
abstract = "We have investigated the effect of cis-diamminedichloroplatinum(II) (CDDP) on signal transduction pathways. CDDP treatment did not cause any change in the binding of [3H]phorbol dibutyrate to PC-9 (human lung adenocarcinoma cell line) cells, a measure of protein kinase C activation. However, 2-h CDDP treatment (20 μg/ml) caused ∼ 200{\%} increase in 1,2-sn-diacylglycerol (DAG) production and ∼ 50{\%} decrease in inositol 1,4,5-triphosphate production. To explore the different source of DAG, we analyzed phospholipids labeled with [14C]choline by TLC and revealed that [14C]choline-labeled phosphatidylcholine (PC) was decreased to 50{\%} by CDDP treatment. This suggested that PC turnover was increased by CDDP-treatment. PC-specific phospholipase C (PC-PLC) activity was increased to 2.5-fold (2.58±0.28 nmol/mg protein per min) by 2 h CDDP (20 μg/ml) treatment compared with control (1.05±0.24 nmol/mg protein per min). Treatment of CDDP also stimulated PC-PLC in the crude membrane extract from PC-9 cells. CDDP had no effect on the activities of phospholipase A2 and D. Trans-DDP, which has far less cytotoxicity than its stereoisomer, CDDP, did not cause any change in PC-PLC activity. A significant inhibition of DNA synthesis (< 80{\%}) occurred 4 h after 2 h CDDP (20 μg/ml) treatment. These results demonstrated that CDDP-induced PC-PLC activation was an early event in CDDP-induced cytotoxicity and suggested that the effects of CDDP on signal transduction pathways had an important role in CDDP-induced cytotoxicity.",
keywords = "cis-diam-minedichloroplatinum(II), Phosphatidylcholine, Phospholipase C",
author = "Kazuto Nishio and Yoshikazu Sugimoto and Yasuhiro Fujiwara and Tohru Ohmori and Toshihiko Morikage and Yuichiro Takeda and Masahiro Ohata and Nagahiro Saijo",
year = "1992",
language = "English",
volume = "89",
pages = "1622--1628",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Phospholipase C-mediated hydrolysis of phosphatidylcholine is activated by cis-diamminedichloroplatinum(II)

AU - Nishio, Kazuto

AU - Sugimoto, Yoshikazu

AU - Fujiwara, Yasuhiro

AU - Ohmori, Tohru

AU - Morikage, Toshihiko

AU - Takeda, Yuichiro

AU - Ohata, Masahiro

AU - Saijo, Nagahiro

PY - 1992

Y1 - 1992

N2 - We have investigated the effect of cis-diamminedichloroplatinum(II) (CDDP) on signal transduction pathways. CDDP treatment did not cause any change in the binding of [3H]phorbol dibutyrate to PC-9 (human lung adenocarcinoma cell line) cells, a measure of protein kinase C activation. However, 2-h CDDP treatment (20 μg/ml) caused ∼ 200% increase in 1,2-sn-diacylglycerol (DAG) production and ∼ 50% decrease in inositol 1,4,5-triphosphate production. To explore the different source of DAG, we analyzed phospholipids labeled with [14C]choline by TLC and revealed that [14C]choline-labeled phosphatidylcholine (PC) was decreased to 50% by CDDP treatment. This suggested that PC turnover was increased by CDDP-treatment. PC-specific phospholipase C (PC-PLC) activity was increased to 2.5-fold (2.58±0.28 nmol/mg protein per min) by 2 h CDDP (20 μg/ml) treatment compared with control (1.05±0.24 nmol/mg protein per min). Treatment of CDDP also stimulated PC-PLC in the crude membrane extract from PC-9 cells. CDDP had no effect on the activities of phospholipase A2 and D. Trans-DDP, which has far less cytotoxicity than its stereoisomer, CDDP, did not cause any change in PC-PLC activity. A significant inhibition of DNA synthesis (< 80%) occurred 4 h after 2 h CDDP (20 μg/ml) treatment. These results demonstrated that CDDP-induced PC-PLC activation was an early event in CDDP-induced cytotoxicity and suggested that the effects of CDDP on signal transduction pathways had an important role in CDDP-induced cytotoxicity.

AB - We have investigated the effect of cis-diamminedichloroplatinum(II) (CDDP) on signal transduction pathways. CDDP treatment did not cause any change in the binding of [3H]phorbol dibutyrate to PC-9 (human lung adenocarcinoma cell line) cells, a measure of protein kinase C activation. However, 2-h CDDP treatment (20 μg/ml) caused ∼ 200% increase in 1,2-sn-diacylglycerol (DAG) production and ∼ 50% decrease in inositol 1,4,5-triphosphate production. To explore the different source of DAG, we analyzed phospholipids labeled with [14C]choline by TLC and revealed that [14C]choline-labeled phosphatidylcholine (PC) was decreased to 50% by CDDP treatment. This suggested that PC turnover was increased by CDDP-treatment. PC-specific phospholipase C (PC-PLC) activity was increased to 2.5-fold (2.58±0.28 nmol/mg protein per min) by 2 h CDDP (20 μg/ml) treatment compared with control (1.05±0.24 nmol/mg protein per min). Treatment of CDDP also stimulated PC-PLC in the crude membrane extract from PC-9 cells. CDDP had no effect on the activities of phospholipase A2 and D. Trans-DDP, which has far less cytotoxicity than its stereoisomer, CDDP, did not cause any change in PC-PLC activity. A significant inhibition of DNA synthesis (< 80%) occurred 4 h after 2 h CDDP (20 μg/ml) treatment. These results demonstrated that CDDP-induced PC-PLC activation was an early event in CDDP-induced cytotoxicity and suggested that the effects of CDDP on signal transduction pathways had an important role in CDDP-induced cytotoxicity.

KW - cis-diam-minedichloroplatinum(II)

KW - Phosphatidylcholine

KW - Phospholipase C

UR - http://www.scopus.com/inward/record.url?scp=0026724167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026724167&partnerID=8YFLogxK

M3 - Article

C2 - 1569201

AN - SCOPUS:0026724167

VL - 89

SP - 1622

EP - 1628

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -