Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes

Genevieve L. Coe, Priscilla S. Redd, Amy V. Paschall, Chunwan Lu, Lilly Gu, Houjian Cai, Thomas Albers, Iryna O. Lebedyeva, Kebin Liu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-ΰ B, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.

Original languageEnglish (US)
Article number30816
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 4 2016

Fingerprint

Caspase 8
Ceramides
Cytotoxic T-Lymphocytes
Colon
Carcinoma
Neoplasms
Apoptosis
Immunotherapy
Colonic Neoplasms
Cell Death

ASJC Scopus subject areas

  • General

Cite this

Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. / Coe, Genevieve L.; Redd, Priscilla S.; Paschall, Amy V.; Lu, Chunwan; Gu, Lilly; Cai, Houjian; Albers, Thomas; Lebedyeva, Iryna O.; Liu, Kebin.

In: Scientific Reports, Vol. 6, 30816, 04.08.2016.

Research output: Contribution to journalArticle

@article{fc18a16ee21241be91e4ad43ea760434,
title = "Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes",
abstract = "FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-{\^I}° B, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.",
author = "Coe, {Genevieve L.} and Redd, {Priscilla S.} and Paschall, {Amy V.} and Chunwan Lu and Lilly Gu and Houjian Cai and Thomas Albers and Lebedyeva, {Iryna O.} and Kebin Liu",
year = "2016",
month = "8",
day = "4",
doi = "10.1038/srep30816",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes

AU - Coe, Genevieve L.

AU - Redd, Priscilla S.

AU - Paschall, Amy V.

AU - Lu, Chunwan

AU - Gu, Lilly

AU - Cai, Houjian

AU - Albers, Thomas

AU - Lebedyeva, Iryna O.

AU - Liu, Kebin

PY - 2016/8/4

Y1 - 2016/8/4

N2 - FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-ΰ B, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.

AB - FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF-ΰ B, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy.

UR - http://www.scopus.com/inward/record.url?scp=84982740524&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982740524&partnerID=8YFLogxK

U2 - 10.1038/srep30816

DO - 10.1038/srep30816

M3 - Article

C2 - 27487939

AN - SCOPUS:84982740524

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 30816

ER -