The Role of the Integrated Response of Tumor Cells to Stress, Autophagy, and Chaperones in the Origin of Recurrent Resistant Tumors

Abstract

Chemotherapy and radiotherapy are a colossal stress factor for tumor cells. In response to therapy, the entire evolutionarily fixed response of cells to stress is activated. This happens at all levels of cell organization, namely at the protein level and the DNA level. This response involves the cell proteostasis system, DNA repair systems, tumor suppressor genes, and many other cell systems. We will consider the role of the main systems of proteostasis in these processes, namely, macroautophagy and chaperones, which are part of the integrated response of the cell to stress. As a result of the cell’s response to stress, the tumor cell becomes even less differentiated, activating the genes and intracellular systems necessary for survival. Cells that have responded to stress in this way have a more aggressive phenotype that is significantly more resistant to therapy. Under the influence of stress, the cell evolutionarily simplifies, which gives it additional chances for survival. On the one hand, autophagy contributes to a decrease in tumor cell differentiation and its plasticity, and on the other hand, it maintains a certain stability, being responsible for the integrity of the genome and freeing the cell from damaged organelles and defective proteins. Both autophagy and chaperones contribute to the acquisition of multidrug resistance by the tumor, which further complicates therapy. Understanding these processes makes it possible to develop new therapeutic approaches, taking into account the multistage nature of carcinogenesis.