Induction of autophagy by valproic acid enhanced lymphoma cell chemosensitivity through HDAC-independent and IP3-mediated PRKAA activation

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.

自噬（Autophagy）与肿瘤细胞对抗癌药物的敏感性密切相关。组蛋白去乙酰化酶（histone deacetylase, HDAC）抑制剂丙戊酸（valproic acid, VPA）可与化疗药物协同作用，诱导淋巴瘤细胞发生自噬，该过程由AMP活化蛋白激酶（AMP-activated protein kinase, AMPK）的激活以及下游雷帕霉素机制性靶标（mechanistic target of rapamycin [serine/threonine kinase], MTOR）信号通路的抑制所介导。在不依赖HDAC的情况下，VPA可通过降低细胞内1,4,5-三磷酸肌醇（inositol 1,4,5 trisphosphate, IP3）水平、阻断钙离子向线粒体内流以及调控PRKAA1/2-MTOR信号级联反应，增强阿霉素（doxorubicin）对淋巴瘤细胞自噬的诱导效果。在淋巴瘤细胞皮下接种构建的小鼠异种移植模型中，VPA与阿霉素联合给药可触发IP3介导的钙离子耗竭与PRKAA1/2激活，诱导原位自噬，并有效抑制肿瘤生长。淋巴瘤患者原发肿瘤中常存在线粒体钙离子转运相关基因的异常改变。综上，本研究结果表明VPA具有不依赖HDAC的化疗增敏活性，为靶向自噬治疗淋巴瘤的临床应用提供了新的理论依据。