التفاصيل البيبلوغرافية
| العنوان: |
Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia |
| المؤلفون: |
Gugliotta, Gabriele, Sudo, Makoto, Cao, Qi, Lin, De-Chen, Sun, Haibo, Takao, Sumiko, Le Moigne, Ronan, Rolfe, Mark, Gery, Sigal, Müschen, Markus, Cavo, Michele, Koeffler, H Phillip |
| المصدر: |
Neoplasia, vol 19, iss 10 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2017 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Pediatric Cancer, Genetics, Hematology, Rare Diseases, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Antineoplastic Agents, Apoptosis, Biomarkers, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Cell Survival, Drug Synergism, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Gene Expression Regulation, Gene Knockout Techniques, Humans, Molecular Targeted Therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Signal Transduction, Unfolded Protein Response, Valosin Containing Protein |
| جغرافية الموضوع: |
750 - 761 |
| الوصف: |
B acute lymphoblastic leukemia (B-ALL) cells are distinctively vulnerable to endoplasmic reticulum (ER) stress. Recently, inhibition of p97 was shown to induce ER stress and subsequently cell death in solid tumors and in multiple myeloma. We investigated the role of a novel, orally available, p97 inhibitor (CB-5083; Cleave Biosciences) in B-ALL. CB-5083 induced a significant reduction in viability in 10 human B-ALL cell lines, harboring the most common fusion-genes involved in pediatric and adult B-ALL, with IC50s ranging from 0.34 to 0.76 μM. Moreover, CB-5083 significantly reduced the colony formation of OP1 and NALM6 cells. Early and strong induction of apoptosis was demonstrated in BALL1 and OP1 cells, together with a robust cleavage of PARP. CB-5083 induced ER stress, as documented through: 1) prominent expression of chaperones (GRP78, GRP94, PDI, DNAJC3, and DNAJB9); 2) increased activation of IRE1-alpha, as demonstrated by the splicing of XBP1; and 3) activation of PERK, which resulted in a significant overexpression of CHOP, and its downstream genes. CB-5083 reduced the viability also in GRP78-/-, GRP94-/-, and XBP1-/- cells, suggesting that none of these proteins alone was strictly required for CB-5083 activity. Moreover, we showed that the absence of XBP1 (XBP1-/-) increased the sensitivity to CB-5083, leading to the hypothesis that XBP1 splicing counteracts the activity of CB-5083, probably mitigating ER stress. Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 cells. In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt33r8b6qq; https://escholarship.org/uc/item/33r8b6qqTest |
| الإتاحة: |
https://escholarship.org/uc/item/33r8b6qqTest |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.C76B7D88 |
| قاعدة البيانات: |
BASE |
