Cancer growth starts in the mitochondria after activation of preexisting tumor genes in the nucleus. Generally, cells generate energy in form of adenosine triphosphate (ATP) in mitochondria through respiration (Marchi et al. 64). However, tumor cells have damaged mitochondria attributed to DNA mutations and inflammation, which renders them inefficient in undertaking respiration process (Danese et al. 621). For this reason, they use fermentation process in the cytoplasm to generate energy (Ježek et al. 13). Two events in the genome, which are gene alteration and epigenetic modifications, lead to acquired drug resistance (Giorgi et al. 714). In addition, melanoma cells use proteins, genes, and altered pathways to survive against drugs.
Calcium ions play a significant role of activating and enhancing cell death in tumor cells. It is also a mediator in several signaling pathway (Zhai et al. 1536). The apoptosis and proliferation process of cancer cells is depended on (Ca2 +) concentration (Srinivasan et al. 606). The cytosolic Ca2 + signals is controlled by activities such as import of Ca2 + into the cell, export of Ca2 + out of the cell, and Ca2 + buffering in the cell. These mechanisms regulate the processes og activation, proliferation, and apoptosis (Kania et al. 140). Short-lived small elevations of cytosolic Ca2 + increase cell proliferation, while continual ones lead to cell death.
The resistance of cancer cells to drugs has been explained using two models, which are environment-mediated drug resistance (EMDR) and the cancer stem model (CSC). The EMDR occurs when the cell interacts with the environment and enters a dormant state to circumvent therapy (Mansoori et al. 341). In CSC model, cancer cells deviate from normal tissues through dysregulation of self-renewal pathways. It involves various mechanism such as changing drug metabolism and transport, drug targets mutation, and genetic rewiring, which leads to impaired apoptosis and tumor cells resistance against treatment.
Giorgi, Carlotta et al. “The Machineries, Regulation and Cellular Functions of Mitochondrial Calcium.” Nature Reviews Molecular Cell Biology, vol. 19, no. 11, 2018, pp. 713-730.
Danese, Alberto, et al. “Calcium Regulates Cell Death in Cancer: Roles of the Mitochondria and Mitochondria-associated Membranes (MAMs).” Biochimica et Biophysica Acta (BBA)-Bioenergetics, vol. 1858, no. 8, 2017, pp. 615-627.
Ježek, Jan et al.. “Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression.” Antioxidants, vol. 7, no. 1, 2018, p. 13.
Kania, Elzbieta, et al. “IP3 Receptor-mediated Calcium Signaling and Its Role in Autophagy in Cancer.” Frontiers in Oncology, no. 7, 2017, p. 140.
Mansoori, Behzad, et al. “The Different Mechanisms of Cancer Drug Resistance: A Brief Review.” Advanced Pharmaceutical Bulletin, vol.7, no. 3, 2017, pp. 339-348.
Marchi, Saverio, et al. “Mitochondrial and Endoplasmic Reticulum Calcium Homeostasis and Cell Death.” Cell Calcium, no. 69, 2018, pp. 62-72.
Srinivasan, Satish, et al. “Mitochondrial Dysfunction and Mitochondrial Dynamics-The Cancer Connection.” Biochimica et Biophysica Acta (BBA)-Bioenergetics, vol. 1858, no. 8, 2017, pp. 602-614.
Zhai, Xingjian et al.. “Lessons from the Endoplasmic Reticulum Ca2+ Transporters—A Cancer Connection.” Cells, vol. 9, no. 6, 2020, p. 1536.