Raptinal Induces Gasdermin E-Dependent Pyroptosis in Naïve and Therapy-Resistant Melanoma.
Mol Cancer Res
; 20(12): 1811-1821, 2022 12 02.
Article
in En
| MEDLINE
| ID: mdl-36044013
ABSTRACT
Lack of response and acquired resistance continue to be limitations of targeted and immune-based therapies. Pyroptosis is an inflammatory form of cell death characterized by the release of inflammatory damage-associated molecular patterns (DAMP) and cytokines via gasdermin (GSDM) protein pores in the plasma membrane. Induction of pyroptosis has implications for treatment strategies in both therapy-responsive, as well as resistance forms of melanoma. We show that the caspase-3 activator, raptinal, induces pyroptosis in both human and mouse melanoma cell line models and delays tumor growth in vivo. Release of DAMPs and inflammatory cytokines was dependent on caspase activity and GSDME expression. Furthermore, raptinal stimulated pyroptosis in melanoma models that have acquired resistance to BRAF and MEK inhibitor therapy. These findings add support to efforts to induce pyroptosis in both the treatment-naïve and resistant settings. IMPLICATIONS Raptinal can rapidly induce pyroptosis in naïve and BRAFi plus MEKi-resistant melanoma, which may be beneficial for patients who have developed acquired resistance to targeted therapies.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyroptosis
/
Melanoma
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Cancer Res
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2022
Type:
Article