Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Induction of Breast Cancer Cell Apoptosis by TRAIL and Smac Mimetics : Involvement of RIP1 and cFLIP

Holmgren, Christian LU ; Sunström Thörnberg, Ellen ; Granqvist, Victoria LU and Larsson, Christer LU (2022) In Current Issues in Molecular Biology 44(10). p.4803-4821
Abstract

Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are however not fully understood. In this study, we aimed to shed light on these mechanisms in breast cancer cells. Three breast cancer cell lines, MDA-MB-468, CAMA-1 and MCF-7, were used to evaluate the effects of Smac mimetic LCL-161 and TRAIL using cell death assays and Western blot. The combination treatment induces apoptosis and caspase-8 cleavage in MDA-MB-468 and CAMA-1 but not in MCF-7 cells and downregulation of caspase-8 blocked... (More)

Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are however not fully understood. In this study, we aimed to shed light on these mechanisms in breast cancer cells. Three breast cancer cell lines, MDA-MB-468, CAMA-1 and MCF-7, were used to evaluate the effects of Smac mimetic LCL-161 and TRAIL using cell death assays and Western blot. The combination treatment induces apoptosis and caspase-8 cleavage in MDA-MB-468 and CAMA-1 but not in MCF-7 cells and downregulation of caspase-8 blocked apoptosis. Downregulation, but not kinase inhibition, of receptor-interacting protein 1 (RIP1) suppressed apoptosis in CAMA-1. Apoptosis is preceded by association of RIP1 with caspase-8. Downregulating cellular FLICE-like inhibitory protein (c-FLIP) resulted in increased caspase cleavage and some induction of apoptosis by TRAIL and LCL-161 in MCF-7. In CAMA-1, c-FLIP depletion potentiated TRAIL-induced caspase cleavage and LCL-161 did not increase it further. Our results lend further support to a model where LCL-161 enables the formation of a complex including RIP1 and caspase-8 and circumvents c-FLIP-mediated inhibition of caspase activation.

(Less)
Please use this url to cite or link to this publication:
author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
apoptosis, breast cancer, c-FLIP, RIP1, Smac mimetic, TRAIL
in
Current Issues in Molecular Biology
volume
44
issue
10
pages
19 pages
publisher
MDPI AG
external identifiers
  • scopus:85140605050
  • pmid:36286042
ISSN
1467-3037
DOI
10.3390/cimb44100327
language
English
LU publication?
yes
id
892197d7-c0e3-4282-90ce-4fda0da00349
date added to LUP
2022-12-14 12:20:52
date last changed
2024-06-09 16:15:19
@article{892197d7-c0e3-4282-90ce-4fda0da00349,
  abstract     = {{<p>Smac mimetics are a group of compounds able to facilitate cell death in cancer cells. TNF-related apoptosis-inducing ligand (TRAIL) is a death receptor ligand currently explored in combination with Smac mimetics. The molecular mechanisms determining if the combination treatment results in apoptosis are however not fully understood. In this study, we aimed to shed light on these mechanisms in breast cancer cells. Three breast cancer cell lines, MDA-MB-468, CAMA-1 and MCF-7, were used to evaluate the effects of Smac mimetic LCL-161 and TRAIL using cell death assays and Western blot. The combination treatment induces apoptosis and caspase-8 cleavage in MDA-MB-468 and CAMA-1 but not in MCF-7 cells and downregulation of caspase-8 blocked apoptosis. Downregulation, but not kinase inhibition, of receptor-interacting protein 1 (RIP1) suppressed apoptosis in CAMA-1. Apoptosis is preceded by association of RIP1 with caspase-8. Downregulating cellular FLICE-like inhibitory protein (c-FLIP) resulted in increased caspase cleavage and some induction of apoptosis by TRAIL and LCL-161 in MCF-7. In CAMA-1, c-FLIP depletion potentiated TRAIL-induced caspase cleavage and LCL-161 did not increase it further. Our results lend further support to a model where LCL-161 enables the formation of a complex including RIP1 and caspase-8 and circumvents c-FLIP-mediated inhibition of caspase activation.</p>}},
  author       = {{Holmgren, Christian and Sunström Thörnberg, Ellen and Granqvist, Victoria and Larsson, Christer}},
  issn         = {{1467-3037}},
  keywords     = {{apoptosis; breast cancer; c-FLIP; RIP1; Smac mimetic; TRAIL}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{4803--4821}},
  publisher    = {{MDPI AG}},
  series       = {{Current Issues in Molecular Biology}},
  title        = {{Induction of Breast Cancer Cell Apoptosis by TRAIL and Smac Mimetics : Involvement of RIP1 and cFLIP}},
  url          = {{http://dx.doi.org/10.3390/cimb44100327}},
  doi          = {{10.3390/cimb44100327}},
  volume       = {{44}},
  year         = {{2022}},
}