Figure 4.

The autophagy/mitophagy and apoptosis of tumor cells. Autophagy plays a key role in maintaining cellular homeostasis. Autophagy disorder destroys normal physiological processes and can lead to cancer. Ca²⁺ can inhibit autophagy through an IP3R- or ER-mediated manner. Some mitochondrial Ca²⁺ transporters are also involved in autophagy and mitophagy regulation. Autophagy plays two roles in a tumor: a protective role in the early stages of tumor and the promotion of tumor growth in advanced stages. Tumor cells may avoid apoptosis by reducing Ca²⁺ influx into the cytoplasm. It can be achieved by downregulation of the expression of Ca²⁺ channels in the plasma membrane or by reducing the effectiveness of the signal pathways that activate these channels. This protective measure will greatly reduce the response of Ca²⁺ overload to pro-apoptotic stimulus, thus impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways in tumor cells. Another mechanism is that tumor cells adapt to the reduction of Ca²⁺ in ER, without inducing the pro-apoptotic ER stress response usually accompanied by ER Ca²⁺ imbalance. ER, endoplasmic reticulum; MAM, mitochondrial-associated ER membrane; MCU, mitochondrial calcium uniporter; MPTP, mitochondrial permeability transition pore; ROS, reactive oxygen species; TRPM8, transient receptor potential cation channel subfamily M member 8; VDAC, voltage-dependent anion-selective channel; SERCA, sarco-endoplasmic reticulum Ca²⁺-ATPase; IP3R, inositol triphosphate receptor; BRCA1, breast cancer susceptibility gene.