Heightened JNK Activation and Reduced XIAP Levels Promote TRAIL and Sunitinib-Mediated Apoptosis in Colon Cancer Models.
Apoptosis
TRAIL
XIAP
colon cancer
sunitinib
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
26 Jun 2019
26 Jun 2019
Historique:
received:
03
05
2019
revised:
20
06
2019
accepted:
22
06
2019
entrez:
29
6
2019
pubmed:
30
6
2019
medline:
30
6
2019
Statut:
epublish
Résumé
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis that may be a promising agent in cancer therapy due to its selectivity toward tumor cells. However, many cancer cells are resistant to TRAIL due to defects in apoptosis signaling or activation of survival pathways. We hypothesized that a disruption of pro-survival signaling cascades with the multi-tyrosine kinase inhibitor sunitinib and would be an effective strategy to enhance TRAIL-mediated apoptosis. Here we demonstrate that sunitinib significantly augments the anticancer activity of TRAIL in models of colon cancer. The therapeutic benefit of the TRAIL/sunitinib combination was associated with increased apoptosis marked by enhanced caspase-3 cleavage and DNA fragmentation. Overexpression of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2) in HCT116 cells reduced TRAIL/sunitinib-mediated apoptosis, further supporting that sunitinib enhances the anticancer activity of TRAIL via augmented apoptosis. Analysis of pro-survival factors identified that the combination of TRAIL and sunitinib significantly downregulated the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP) through a c-Jun N-terminal kinase (JNK)-mediated mechanism. Short hairpin RNA (shRNA)-mediated knockdown of JNK confirmed its key role in the regulation of sensitivity to this combination as cells with suppressed JNK expression exhibited significantly reduced TRAIL/sunitinib-mediated apoptosis. Importantly, the therapeutic benefit of the TRAIL/sunitinib combination was validated in the HCT116-Luc and HCT15 colon cancer xenograft models, which both demonstrated significant anti-tumor activity in response to combination treatment. Collectively, our data demonstrate that sunitinib enhances TRAIL-mediated apoptosis by heightened JNK activation, diminished XIAP levels, and augmented apoptosis.
Identifiants
pubmed: 31248045
pii: cancers11070895
doi: 10.3390/cancers11070895
pmc: PMC6678293
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : National Cancer Institute
ID : R01CA190789
Organisme : National Cancer Institute
ID : R01CA172443
Organisme : Congressionally Directed Medical Research Programs
ID : W81XWH-07-2-0025
Organisme : National Cancer Institute
ID : P30CA023074
Organisme : NCI NIH HHS
ID : R01 CA190789
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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