Microtubule-interfering agents activate c-Jun N-terminal kinase/stress- activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways

The essential cellular functions associated with microtubules have led to a wide use of microtubule-interfering agents in cancer chemotherapy with promising results. Although the most well studied action of microtubule- interfering agents is an arrest of cells at the G₂/M phase of the cell cycle, other effects may also exist. We have observed that paclitaxel (Taxol), docetaxel (Taxotere), vinblastine, vincristine, nocodazole, and colchicine activate the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signaling pathway in a variety of human cells. Activation of JNK/SAPK by microtubule-interfering agents is dose-dependent and time- dependent and requires interactions with microtubules. Functional activation of the JNKK/SEK1-JNK/SAPK-c-Jun cascade (where NKK/SEK1 is JNK kinase/SAPK kinase) was demonstrated by activation of a 12-O-tetradecanoylphorbol-13- acetate response element (TRE) reporter construct in a c-Jun dependent fashion. Microtubule-interfering agents also activated both Ras and apoptosis signal-regulating kinase (ASK1) and coexpression of dominant negative Ras and dominant negative apoptosis signal-regulating kinase exerted individual and additive inhibition of JNK/SAPK activation by microtubule-interfering agents. These findings suggest that multiple signal transduction pathways are involved with cellular detection of microtubular disarray and subsequent activation of JNK/SAPK.