期刊
MOLECULAR PHARMACEUTICS
卷 14, 期 11, 页码 4042-4051出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00710
关键词
lymphoma; cholesterol; high-density lipoproteins; nanoparticles; B-cell receptor signaling
资金
- Northwestern University Flow Cytometry Core Facility
- Cancer Center Support Grant [NCI CA060553]
- Northwestern University Immunobiology Center Flow Cytometry Core Facility
- National Institutes of Health/National Heart, Lung, and Blood Institute from the Vascular Surgery Scientist Training Program [T32HL094293]
- NIH [CA073507, R01CA167041]
- Brookstone Research Fund
- Lymphoma Research Fund
- NHLBI [R01HL116577]
- Howard Hughes Medical Institute (HHMI)
- Department of Defense/Air Force Office of Scientific Research [FA95501310192]
- National Institutes of Health/National Cancer Institute [U54CA151880]
Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is, an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differeritial cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.
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