Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells

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Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells. / König, Corinna; Ivanisenko, Nikita V.; Ivanisenko, Vladimir A. и др.

в: Communications Biology, Том 8, № 1, 4, 03.01.2025.

Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование

BibTeX

@article{78268aa92d6c419ebe19a1d49149c099,

title = "Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells",

abstract = "Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.",

keywords = "Humans, Pancreatic Neoplasms/drug therapy, Caspase 8/metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism, Cell Line, Tumor, Deoxycytidine/analogs & derivatives, Apoptosis/drug effects, Gemcitabine, Protein Multimerization/drug effects, TNF-Related Apoptosis-Inducing Ligand/pharmacology, Pyrimidines, Thiophenes",

author = "Corinna K{\"o}nig and Ivanisenko, {Nikita V.} and Ivanisenko, {Vladimir A.} and Dagmar Kulms and Lavrik, {Inna N.}",

year = "2025",

month = jan,

day = "3",

doi = "10.1038/s42003-024-07409-6",

language = "English",

volume = "8",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

}

RIS

TY - JOUR

T1 - Pharmacological targeting of caspase-8/c-FLIPL heterodimer enhances complex II assembly and elimination of pancreatic cancer cells

AU - König, Corinna

AU - Ivanisenko, Nikita V.

AU - Ivanisenko, Vladimir A.

AU - Kulms, Dagmar

AU - Lavrik, Inna N.

PY - 2025/1/3

Y1 - 2025/1/3

N2 - Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.

AB - Extrinsic apoptotic network is driven by Death Ligand (DL)-mediated activation of procaspase-8. Recently, we have developed the first-in class small molecule, FLIPinB, which specifically targets the key regulator of extrinsic apoptosis, the protein c-FLIPL, in the caspase-8/c-FLIPL heterodimer. We have shown that FLIPinB enhances DL-induced caspase-8 activity and apoptosis. However, the effects of FLIPinB action in combination with other cell death inducers have only just begun to be elucidated. Here, we show that FLIPinB enhances the cell death in pancreatic cancer cells induced by combinatorial treatment with DL, gemcitabine and Mcl-1 inhibitor S63845. Further, we found that these effects are mediated via an increase in the complex II assembly. Collectively, our study shows that targeting the caspase-8/c-FLIPL heterodimer in combination with the other drugs in pancreatic cancer cells is a promising direction that may provide a basis for further therapeutic strategies.

KW - Humans

KW - Pancreatic Neoplasms/drug therapy

KW - Caspase 8/metabolism

KW - CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism

KW - Cell Line, Tumor

KW - Deoxycytidine/analogs & derivatives

KW - Apoptosis/drug effects

KW - Gemcitabine

KW - Protein Multimerization/drug effects

KW - TNF-Related Apoptosis-Inducing Ligand/pharmacology

KW - Pyrimidines

KW - Thiophenes

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85214033943&origin=inward&txGid=147faf415dbfedfc6d57e29488490a06

UR - https://www.mendeley.com/catalogue/1d16c681-dabd-3330-b26b-a57dd7ae7b31/

UR - https://pubmed.ncbi.nlm.nih.gov/39753884/

U2 - 10.1038/s42003-024-07409-6

DO - 10.1038/s42003-024-07409-6

M3 - Article

C2 - 39753884

VL - 8

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 4

ER -

ID: 62833364