Stromal cell protein kinase C-ß inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance.
Sci Transl Med
; 12(526)2020 01 15.
Article
in En
| MEDLINE
| ID: mdl-31941829
ABSTRACT
Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-ß-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-ß inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-ß controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal-regulated kinase (ERK)-mediated stabilization of B cell lymphoma-extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-ß-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-ß, enhance the effectiveness of many antileukemic therapies.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinase C beta
Limits:
Humans
Language:
En
Journal:
Sci Transl Med
Journal subject:
CIENCIA
/
MEDICINA
Year:
2020
Document type:
Article
Affiliation country:
Reino Unido