Inhibiting TNF-mediated signaling: A novel therapeutic paradigm for androgen independent prostate cancer

Sowmyalakshmi Srinivasan, Raj Kumar, Srinivas Koduru, Aaditya Chandramouli, Chendil Damodaran

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-α and its downstream prosurvival signaling molecules such as NF-κB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-α and NF-κB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

Original languageEnglish (US)
Pages (from-to)153-161
Number of pages9
JournalApoptosis
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Androgens
Prostatic Neoplasms
Tumor Necrosis Factor-alpha
Cells
Apoptosis
Therapeutics
Tumors
Neoplasms
Cell Survival
Death Domain Receptors
Oncology
Tumor Necrosis Factor Receptors
Caspases
Heterografts
Oral Administration
Toxicity
psoralidin
Chemical activation
Monoclonal Antibodies
Pharmacology

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

Cite this

Srinivasan, Sowmyalakshmi ; Kumar, Raj ; Koduru, Srinivas ; Chandramouli, Aaditya ; Damodaran, Chendil. / Inhibiting TNF-mediated signaling : A novel therapeutic paradigm for androgen independent prostate cancer. In: Apoptosis. 2010 ; Vol. 15, No. 2. pp. 153-161.
@article{19b49a56e6ab45878fb67035fecdbcb1,
title = "Inhibiting TNF-mediated signaling: A novel therapeutic paradigm for androgen independent prostate cancer",
abstract = "The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-α and its downstream prosurvival signaling molecules such as NF-κB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-α and NF-κB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.",
author = "Sowmyalakshmi Srinivasan and Raj Kumar and Srinivas Koduru and Aaditya Chandramouli and Chendil Damodaran",
year = "2010",
month = "2",
day = "1",
doi = "10.1007/s10495-009-0416-9",
language = "English (US)",
volume = "15",
pages = "153--161",
journal = "Apoptosis : an international journal on programmed cell death",
issn = "1360-8185",
publisher = "Springer Netherlands",
number = "2",

}

Inhibiting TNF-mediated signaling : A novel therapeutic paradigm for androgen independent prostate cancer. / Srinivasan, Sowmyalakshmi; Kumar, Raj; Koduru, Srinivas; Chandramouli, Aaditya; Damodaran, Chendil.

In: Apoptosis, Vol. 15, No. 2, 01.02.2010, p. 153-161.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibiting TNF-mediated signaling

T2 - A novel therapeutic paradigm for androgen independent prostate cancer

AU - Srinivasan, Sowmyalakshmi

AU - Kumar, Raj

AU - Koduru, Srinivas

AU - Chandramouli, Aaditya

AU - Damodaran, Chendil

PY - 2010/2/1

Y1 - 2010/2/1

N2 - The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-α and its downstream prosurvival signaling molecules such as NF-κB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-α and NF-κB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

AB - The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-α and its downstream prosurvival signaling molecules such as NF-κB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-α and NF-κB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

UR - http://www.scopus.com/inward/record.url?scp=77949270814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949270814&partnerID=8YFLogxK

U2 - 10.1007/s10495-009-0416-9

DO - 10.1007/s10495-009-0416-9

M3 - Article

C2 - 19851870

AN - SCOPUS:77949270814

VL - 15

SP - 153

EP - 161

JO - Apoptosis : an international journal on programmed cell death

JF - Apoptosis : an international journal on programmed cell death

SN - 1360-8185

IS - 2

ER -