In a recent study published online in Cell Death and Differentiation on Oct 23, a research group led by Dr. SUN Liming at the CAS Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences reported microtubule-targeting agents (MTAs) induce programmed cell death via membrane- bound TNF.
MTAs are a class of most widely used chemotherapeutics. Whether MTAs can directly induce cell death has been long debated and their mechanism of action remains elusive. MTAs are assumed to induce mitotic arrest in rapidly dividing tumor cells, resulting in so called ‘mitotic catastrophe’ and cell death. However, the mitotic arrest dogma cannot fully explain how MTAs induce the entire slowly growing tumor regression by targeting only a small fraction of the tumor mass (dividing cells). In addition, considering the widely existence of microtubules in both dividing and non-dividing cells, it raises the possibility that MTAs may affect the interphase cellular processes to induce extensive tumor cell death.
The study revealed the mechanism of action of MTAs and found MTAs function by inducing membrane accumulation of the 26 kDa membrane-bound TNF (memTNF) and activating TNFR1-mediated cancer-cell-to-cancer-cell killing. The researchers showed that MTAs activate the JNK/c-Jun signaling to induce Jun and Tnf transcriptional upregulation. The membrane accumulated memTNF subsequently initiates TNFR1-dependent programmed cell death (PCD) in bystander cells. In necroptosis-sensitive cells, MTAs directly induce RIP1-RIP3-MLKL-dependent necroptosis, which requires RIP1/RIP3 kinase activity and the phosphorylation of MLKL. MTA-induced PCD is determined by the expression status of RIP3 in human carcinoma cells. In RIP3-deficient cancer cells, long term treatment of MTAs induces TNFR1-dependent apoptosis. With respect to optimizing MTAs application, the researchers showed that MTAs and IAP antagonists combinatory treatment leads to massive memTNF-mediated apoptosis in a broad spectrum of human carcinoma cells representing different histotypes. In addition, taking advantage of patient derived xenograft (PDX) models, we found paclitaxel (Taxol®) and LCL161 combinatory treatment induces effective tumor regression via memTNF-mediated apoptosis. The combined therapy is of high biosafety andthere’s no significant toxicity even after one-month treatment in wild type mice.
This work was financially supported by the Strategic Priority Research Program of the Chinese Academy of Science, the National Key Research and Development Program of China, the NSFC grants, the National Basic Research Program of China 973 Program, and Shanghai Rising-Star Program.
Reference：https://www.nature.com/articles/s41418-019-0441-3
Contact：liming.sun@sibcb.ac.cn
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