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Halting pro-survival autophagy by TGFβ inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) β. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3)-II and inhibiting p62 and phospho-mammalian target of rapamycin. The small-interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFβ mediates bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
medicine.medical_treatment
RNA-Binding Protein
Pyrrole
Antineoplastic Agent
Bortezomib
Bort
Mice
Transforming Growth Factor beta
Drug Combination
Aged, 80 and over
biology
TOR Serine-Threonine Kinase
TOR Serine-Threonine Kinases
RNA-Binding Proteins
Hematology
Middle Aged
Gene Expression Regulation, Neoplastic
Drug Combinations
medicine.anatomical_structure
Oncology
Bone Marrow Cell
Fibroblast
Plasma Cell
Female
Survival Analysi
Multiple Myeloma
Microtubule-Associated Proteins
medicine.drug
Human
Signal Transduction
Xenograft Model Antitumor Assay
Plasma Cells
Primary Cell Culture
Antineoplastic Agents
Bone Marrow Cells
03 medical and health sciences
medicine
Autophagy
Animals
Humans
Pyrroles
Aged
Animal
Growth factor
Microtubule-Associated Protein
Transforming growth factor beta
Fibroblasts
Molecular biology
Survival Analysis
Xenograft Model Antitumor Assays
030104 developmental biology
Apoptosis
Drug Resistance, Neoplasm
Pyrazole
biology.protein
Cancer research
Pyrazoles
Bone marrow
Transforming growth factor
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....29e0d49fd3b043904a4787cc853c0fca