Endoplasmic reticulum-associated calcium regulates taxol-induced apoptosis in breast cancer cells.

Abstract

Abstract Abstract #4163 Background: The body eliminates unhealthy cells through programmed cell-suicide called apoptosis. Calcium (Ca2+), one of the key regulators of cell survival, is also important in regulating apoptosis. Although the chemotherapeutic agent Taxol employs apoptosis to induce cell death in breast cancer treatment, the exact mechanism of how it induces apoptosis and the role of Ca2+ in this process remain unclear. The endoplasmic reticulum (ER), the main intracellular Ca2+ store, is newly-recognized as an important gateway in apoptosis, and possibly provides a target for Taxol.
 Objective/Hypothesis: Putting these facts together, our hypothesis is that ER Ca2+ changes induced by Taxol determine breast cancer cell susceptibility to apoptosis and thus play a key role in ER-associated apoptosis. Therefore, this study investigated whether Ca2+ changes, especially associated with the ER, were generated and related to this apoptotic event.
 Study Design and Methods: For this study, we used the MDA-MB-468 breast cancer cell line. The dynamic Ca2+ changes induced by Taxol were determined in living breast cancer cells by two methods: free cytosolic Ca2+ changes were measured using Fluo4-AM Ca2+ dye; and ER Ca2+ changes were measured by a novel Ca2+ cameleon, D1ER. After inducing and evaluating Taxol-induced apoptosis in this breast cancer cell line, the effects of different Ca2+ interfering agents on the apoptotic event were tested to determine whether Taxol-induced apoptosis is Ca2+ dependent.
 Results: Taxol has a direct effect on Ca2+ homeostasis. Taxol induces a rapid ER Ca2+ release and results in a transient increase in cytosolic Ca2+ levels. A gradual ER Ca2+ depletion developed and contributed to the final sustained cytosolic Ca2+ increase. Interfering with these Ca2+ changes inhibited the Taxol-induced apoptosis, indicating that ER Ca2+ promotes Taxol-induced apoptosis.
 Relevance: It is critical to understand the process through which the widely used anticancer agent Taxol induces apoptosis. This research addressed the question of whether intracellular Ca2+ changes play a critical or marginal role in mediating Taxol-induced apoptosis. Elucidating the role of calcium in this process will not only help to clarify the mechanism of Taxol, but also aid in more effective application of Taxol in breast cancer treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4163.