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ERK mediates interferon gamma-induced melanoma cell death.
Champhekar, Ameya; Heymans, Rachel; Saco, Justin; Turon Font, Guillem; Gonzalez, Cynthia; Gao, Anne; Pham, John; Lee, June; Maryoung, Ryan; Medina, Egmidio; Campbell, Katie M; Karin, Daniel; Austin, David; Damioseaux, Robert; Ribas, Antoni.
Afiliação
  • Champhekar A; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. achamphekar@mednet.ucla.edu.
  • Heymans R; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Saco J; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Turon Font G; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
  • Gonzalez C; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Gao A; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Pham J; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Lee J; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Maryoung R; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Medina E; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Campbell KM; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Karin D; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Austin D; Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Damioseaux R; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
  • Ribas A; California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
Mol Cancer ; 22(1): 165, 2023 10 06.
Article em En | MEDLINE | ID: mdl-37803324
ABSTRACT

BACKGROUND:

Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway.

METHODS:

We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.

RESULTS:

We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins.

CONCLUSIONS:

Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Melanoma Limite: Humans Idioma: En Revista: Mol Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Cutâneas / Melanoma Limite: Humans Idioma: En Revista: Mol Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos