کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8456888 | 1548783 | 2017 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia
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کلمات کلیدی
PEIERADUPRB-ALL4-OHTHNA2-Hydroxy-1-naphthaldehyde - 2-هیدروکسی-1-نفتالدئید3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide - 3- (4،5-dimethylthiazol-2-yl) -2،5-difenyltetrazolium bromideMTT - MTTER-Associated Degradation - تخریب ER-Associatedendoplasmic reticulum - شبکه آندوپلاسمی Unfolded protein response - پاسخ پروتئین آشکارPropidium iodide - پروتئین یدیدPolyethylenimine - پلی اتیلن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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 GRP78â/â, GRP94â/â, and XBP1â/â cells, suggesting that none of these proteins alone was strictly required for CB-5083 activity. Moreover, we showed that the absence of XBP1 (XBP1â/â) 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 19, Issue 10, October 2017, Pages 750-761
Journal: Neoplasia - Volume 19, Issue 10, October 2017, Pages 750-761
نویسندگان
Gabriele Gugliotta, Makoto Sudo, Qi Cao, De-Chen Lin, Haibo Sun, Sumiko Takao, Ronan Le Moigne, Mark Rolfe, Sigal Gery, Markus Müschen, Michele Cavo, H. Phillip Koeffler,