Apoptosis of Cortical Neurons Induced by Taxol

Xavier A. Figueroa-Masot
University of Washington
T32ES07032

Background: Taxol is a drug used to treat ovarian, breast, prostate and lung cancers. It is derived from the Yew tree found in forests in the Pacific northwest. Taxol induces apoptosis or programmed cell death in cancer and non-neuronal cell lines presumably by causing cell cycle arrest. Bcl2 is a protein that protects against many forms of apoptosis. However, Bcl2 does not inhibit apoptosis in non-neuronal cell lines induced by microtubule damaging agents such as Taxol. Taxol treatment of non-neuronal cells causes activation of protein kinase called N-terminal c-Jun (JNK) that phosphorylates and inactivates the Bcl2 antiapoptotic activity and contributes to Taxol-induced apoptosis.

Advance: Although Bcl2 is expressed in central nervous system neurons and protects them from some forms of apoptosis the role of Bcl2 phosphorylation in neuronal apoptosis has not been identified. Since JNK has been implicated in neuron apoptosis we might assume on the basis of JNK's activity in non-neuronal cells that JNK activation in neurons may contribute to Taxol-induced apoptosis by phosphorylation and inactivation of Bcl2. However, these investigators demonstrate that Taxol stimulated apoptosis in cortical neurons is independent of Bcl2. This new mechanism requires JNK signaling to the nucleus and inhibition of the phosphatidylinositol 3 (PI 3)-kinase survival pathway.

Implication: This finding suggests that Taxol induces apoptosis in neurons by a mechanism very different from that of non-neuronal cell lines and emphasizes the importance of understanding the apoptotic mechanisms specific for neurons in the central nervous system. These researchers have shown that there are a variety of mechanisms for regulation of apoptosis in neurons that depend on different combinations of survival and proapoptotic kinase pathways. This finding may have implications in the use and development of anticarcinogenic for tumors of neuronal origin.

Publication: Figueroa-Masot XA, Hetman M, Higgins MJ, Kokot N, Xia Z. Taxol induces apoptosis in cortical neurons by a mechanism independent of Bcl-2 phosphorylation. J Neurosci. 2001 Jul 1;21(13):4657-67.