Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors

Bokyung Sung, Sahdeo Prasad, Jayaraj Ravindran, Vivek R. Yadav, Bharat B Aggarwal

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway.

Original languageEnglish (US)
Pages (from-to)1977-1987
Number of pages11
JournalFree Radical Biology and Medicine
Volume53
Issue number10
DOIs
StatePublished - Nov 15 2012

Fingerprint

Death Domain Receptors
Colorectal Neoplasms
Reactive Oxygen Species
Up-Regulation
Cells
Apoptosis
Chemical activation
Proteins
Down-Regulation
CCAAT-Enhancer-Binding Proteins
capsazepine
bcl-2-Associated X Protein
Caspase 9
Caspase 8
Acetylcysteine
Gene Silencing
Esterases
Colonic Neoplasms
Glutathione
Quenching

Keywords

  • Apoptosis
  • Death receptor
  • Free radicals
  • TRAIL
  • TRPV1 antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors. / Sung, Bokyung; Prasad, Sahdeo; Ravindran, Jayaraj; Yadav, Vivek R.; Aggarwal, Bharat B.

In: Free Radical Biology and Medicine, Vol. 53, No. 10, 15.11.2012, p. 1977-1987.

Research output: Contribution to journalArticle

@article{299a973e64dc4217a800edce2f7412b8,
title = "Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors",
abstract = "A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway.",
keywords = "Apoptosis, Death receptor, Free radicals, TRAIL, TRPV1 antagonist",
author = "Bokyung Sung and Sahdeo Prasad and Jayaraj Ravindran and Yadav, {Vivek R.} and Aggarwal, {Bharat B}",
year = "2012",
month = "11",
day = "15",
doi = "10.1016/j.freeradbiomed.2012.08.012",
language = "English (US)",
volume = "53",
pages = "1977--1987",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "10",

}

TY - JOUR

T1 - Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors

AU - Sung, Bokyung

AU - Prasad, Sahdeo

AU - Ravindran, Jayaraj

AU - Yadav, Vivek R.

AU - Aggarwal, Bharat B

PY - 2012/11/15

Y1 - 2012/11/15

N2 - A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway.

AB - A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway.

KW - Apoptosis

KW - Death receptor

KW - Free radicals

KW - TRAIL

KW - TRPV1 antagonist

UR - http://www.scopus.com/inward/record.url?scp=84868551550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868551550&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2012.08.012

DO - 10.1016/j.freeradbiomed.2012.08.012

M3 - Article

C2 - 22922338

AN - SCOPUS:84868551550

VL - 53

SP - 1977

EP - 1987

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 10

ER -