Distinct signaling pathways of microtubule inhibitors – vinblastine and Taxol induce JNK‐dependent cell death but through AP‐1‐dependent and AP‐1‐independent mechanisms, respectively

Abstract

Vinblastine and paclitaxel (Taxol) are widely used chemotherapeutic drugs that inhibit the normal function of microtubules causing mitotic arrest and cell death. Despite these similarities, the signaling pathways that mediate and regulate cell death induced by these agents remain incompletely understood. The purpose of this study was to directly compare the two drugs in terms of their ability to activate components of the c‐Jun N‐terminal protein kinase (JNK) pathway, and to establish the importance of these signaling events in apoptosis induced by these agents. We show that both drugs induce mitotic arrest and subsequent apoptotic cell death with highly similar kinetics and that both activate JNK and induce c‐Jun protein and c‐jun mRNA expression. Surprisingly, vinblastine induced c‐Jun phosphorylation and c‐jun transcriptional activation, although Taxol failed to do so. However, inhibition of JNK or an absence of JNK protected against both vinblastine‐ and Taxol‐induced cell death. These results suggest that although JNK activation plays an important role in cell death induced by both agents, vinblastine and Taxol differ markedly with respect to signaling downstream of JNK, with AP‐1‐dependent and ‐independent mechanisms, respectively. In addition, these results show, contrary to popular belief, that JNK activation is not necessarily accompanied by c‐Jun activation, and thus c‐Jun is not an obligate substrate of JNK.

Paclitaxel induces apoptosis in leukemia cells through a JNK activation-dependent pathway

“…JNK also modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus by phosphorylation of its target proteins (Vlahopoulos and Zoumpourlis, 2004;Waetzig and Herdegen, 2005). JNK activation has been shown in PTX-treated solid tumor cells (Lee et al, 1998;Kolomeichuk et al, 2008). However, the detailed mechanism of JNK in apoptosis procedures remains largely unclear (Shiah et al, 2001;Ohtsuka et al, 2003;Brichese et al, 2004;Wang et al, 2006;Zhang et al, 2006;Small et al, 2007;Selimovic et al, 2008).…”

Estradiol induces JNK-dependent apoptosis in glioblastoma cells

“…The role of JNKs in cancer is indicated by their ability to cause tumor suppression and induce apoptosis in response to certain anti-cancer drugs (21)(22)(23)(24). However, this increased responsiveness to chemotherapeutics is attenuated in advanced tumors, where JNK signaling is impaired, rendering the cells refractory to chemotherapy (22)(23)(24).…”

“…However, this increased responsiveness to chemotherapeutics is attenuated in advanced tumors, where JNK signaling is impaired, rendering the cells refractory to chemotherapy (22)(23)(24). Recently, it has been reported that MEKK1 is one of the 50 genes containing somatic missense and nonsense mutations in various tumors (25), and MEKK1 is required for JNK activation and induction of apoptosis by drugs causing cytoskeletal disruption, indicating the importance of the MEKK1/JNK-dependent apoptotic pathway in carcinogenesis (26).…”

Microtubule-Depolymerizing Agents Used in Antibody–Drug Conjugates Induce Antitumor Immunity by Stimulation of Dendritic Cells

“…In addition, the molecular mechanisms may be located downstream of TLR domain-containing cytosolic adapters. In fact, microtubule-depolymerizing agents can activate the NF-kB and MAPK signaling pathways efficiently (41,42), although no specific receptors have been identified to date. Further experiments are necessary to address this issue and to define the molecular signaling cascades induced by dolastatins.…”