Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions

Zhi Pan,Lauren Gollahon,Andrew Avila

doi:10.3390/ijms15022672

Abstract

Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis.

Highlights

Calcium, an important cellular regulator, has a dual role in the fate of the cell
That normal external calcium conditions are required to maintain cell survival in breast cancer cells, and long-term absence of external calcium alone can result in apoptosis
Either alone can induce apoptosis, no additive or synergistic effects on apoptosis were observed when cells were treated with paclitaxel in the absence of extracellular calcium

Summary

Introduction

An important cellular regulator, has a dual role in the fate of the cell. While stable calcium homeostasis is necessary for normal cell survival, impaired calcium homeostasis is toxic to cells and may induce cell death [1,2,3,4,5,6]. Among various forms of cell death, apoptosis is a major mechanism utilized by chemotherapy agents to kill cancer cells [7,8,9]. Our previous work showed that paclitaxel, an important chemotherapy agent for breast cancer, can directly attack the internal endoplasmic reticulum (ER) calcium store to release apoptosis—promoting calcium signals depending on dosages [22]. We focus on the role of external calcium to fully understand the calcium—regulated mechanisms of paclitaxel-induced apoptosis

Methods

Results

Conclusion