Accordingly, the mitotic arrest dogma cannot explain how a small dose of MTAs can not only target a small fraction of the tumor mass, where cells are actively dividing, but also reduce the mass of entire slowly growing tumors, such as breast cancers. In individual patients, and even at different locations within the same tumor, the cancer cell proliferation rates are very different, and marked mitotic arrest is rarely observed in patients post-MTA treatment. Much of our knowledge about the mechanism of MTAs inhibiting mitosis is exclusively based on the in vitro studies on fast-dividing cells in culture and xenograft models. However, the clinical disappointment of non-MTA mitosis-specific inhibitors that specifically target the mitotic apparatus, such as mitotic kinases, and the fact that MTAs also kill non-dividing cancer cells, raise the possibility that the success of MTAs is perhaps not limited to impeding the completion of chromosome segregation in mitosis MTAs may also target essential interphase cellular processes in cancer. The clinical success of MTAs has been attributed to their ability to interfere with mitosis, resulting in so called ‘mitotic catastrophe’ and cancer cell death. Despite the well-validated role of MTAs in cancer treatment, the fundamental mechanistic question regarding MTA-induced cell death is still not clear. Microtubule-targeting agents (MTAs), one of the most widely used chemotherapeutics, have gained great success in clinics over a long period. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. In contrast to such notion, here we show-in many cancer cell types-MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells.
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