期刊
AUTOPHAGY
卷 11, 期 12, 页码 2160-2171出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1082024
关键词
alpha; catalytic subunit; AMP-activated; autophagy; chemosensitivity; histone deacetylase inhibitor; inositol 1,4,5 trisphosphate; lymphoma; protein kinase; valproic acid
类别
资金
- National Natural Science Foundation of China [81520108003, 81325003, 81201862, 81172254, 81101793]
- Shanghai Commission of Science and Technology [11JC1407300]
- Program of Shanghai Subject Chief Scientists [13XD1402700]
- Collaborative Innovation Center of Systems Biomedicine
- Samuel Waxman Cancer Research Foundation
Autophagy is closely related to tumor cell sensitivity to anticancer drugs. The HDAC (histone deacetylase) inhibitor valproic acid (VPA) interacted synergistically with chemotherapeutic agents to trigger lymphoma cell autophagy, which resulted from activation of AMPK (AMP-activated protein kinase) and inhibition of downstream MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling. In an HDAC-independent manner, VPA potentiated the effect of doxorubicin on lymphoma cell autophagy via reduction of cellular inositol 1,4,5 trisphosphate (IP3), blockade of calcium into mitochondria and modulation of PRKAA1/2-MTOR cascade. In murine xenograft models established with subcutaneous injection of lymphoma cells, dual treatment of VPA and doxorubicin initiated IP3-mediated calcium depletion and PRKAA1/2 activation, induced in situ autophagy and efficiently retarded tumor growth. Aberrant genes involving mitochondrial calcium transfer were frequently observed in primary tumors of lymphoma patients. Collectively, these findings suggested an HDAC-independent chemosensitizing activity of VPA and provided an insight into the clinical application of targeting autophagy in the treatment of lymphoma.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据