Natural compound Oblongifolin C confers gemcitabine resistance in pancreatic cancer by downregulating Src/MAPK/ERK pathways

Gemcitabine (GEM)-induced drug resistance is the major reason for the failure of chemotherapy in pancreatic cancer (PC). In this study, we found that Oblongifolin C (OC) efficiently inhibited PC cell proliferation by inducing G0/G1 arrest and apoptosis. Also, our mechanism study demonstrated that OC...

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Bibliographic Details
Published in:Cell death & disease 2018-05, Vol.9 (5), p.538-13, Article 538
Main Authors: Li, Yang, Xi, Zhichao, Chen, Xiaoqiong, Cai, Shuangfan, Liang, Chen, Wang, Zhen, Li, Yingyi, Tan, Hongsheng, Lao, Yuanzhi, Xu, Hongxi
Format: Article
Language:English
Subjects:
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Antibodies
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell proliferation
Chemosensitization
Chemotherapy
Drug resistance
Extracellular signal-regulated kinase
Gemcitabine
Immunology
Life Sciences
MAP kinase
Metabolic pathways
Pancreatic cancer
Pheochromocytoma cells
Proteasomes
Ubiquitin
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Summary:Gemcitabine (GEM)-induced drug resistance is the major reason for the failure of chemotherapy in pancreatic cancer (PC). In this study, we found that Oblongifolin C (OC) efficiently inhibited PC cell proliferation by inducing G0/G1 arrest and apoptosis. Also, our mechanism study demonstrated that OC re-sensitized the GEM-resistant PC cells through the ubiquitin-proteasome-dependent degradation of Src, and then downregulating the MAPK pathway. Knockdown of Src plus OC resulted in a greater inhibitory effect in GEM-resistant PC cells. In contrast, Src overexpression reversed OC-mediated chemosensitization, thereby implicating Src in the action of OC. Moreover, our in vivo study showed that OC suppressed the tumor growth via the downregulation of Src, and enhanced the chemosensitivity of GEM-resistant PC to GEM. Overall, our results have revealed that OC is applicable as a promising agent for overcoming GEM-resistant PC, especially with aberrant Src expression.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-018-0574-1