Stress management by autophagy: Implications for chemoresistance

Abstract

Development of chemoresistance, which limits the efficiency of anticancer agents, has long been a major problem in cancer therapy and urgently needs to be solved to improve clinical outcomes. Factors contributing to chemoresistance are various, but a key factor is the cell's capability for stress management. Autophagy, a favored survival strategy that organisms employ to get over many kinds of stress, is emerging as a crucial player in drug resistance. It has been shown that autophagy facilitates the resistance of tumor cells to anticancer agents, and abrogation of autophagy could be therapeutically beneficial in some cases, suggesting autophagy could be a promising target for cancer treatments. Thus, defining the roles of autophagy in chemoresistance, and the mechanisms involved, will be critical to enhance the efficiency of chemotherapy and develop novel anticancer strategy interventions.Over the past decades, chemotherapeutic drugs have been widely used in a variety of cancer treatments. Research efforts to improve chemotherapy have had extraordinary success: however, a common clinical issue is that resistance to such anticancer agents occurs in nearly all types of cancer, which may lead to treatment failure. 1,2 The mechanism by which chemoresistance develops is under intense investigation, and a number of factors including drug transporting, cancer cell heterogeneity, target mutation as well as the tumor microenvironment have been identified. [3][4][5][6] Apart from these mechanisms, the capacity of tumor cells themselves to handle the stress induced by chemotherapeutic agents is noteworthy. During evolution, cells have developed efficient defense machinery to survive under adverse environments, but cancer cells may actually utilize this protective mechanism to overcome anticancer drug-induced stress that is key reason for chemoresistance.Macroautophagy, hereafter refer to as autophagy, is an evolutionarily conserved cellular degradation process in which damaged organelles and protein aggregates are sequestered in a double membrane vesicle followed by fusion with lysosomes, whereby the cargo is degraded and recycled. 7 It is well accepted that autophagy plays essential homeostatic roles, providing cells the energy and synthesis materials to meet their metabolic needs and cope with severe stress, 8 suggesting it may be involved in development of chemoresistance. However, many chemotherapeutic drugs also show significant coordination effects on autophagy, whereby modulating autophagy can influence the anticancer effects to some degree. 9-11 Regulation of autophagy and stress response involves multiple signaling pathways that have also been implicated in tumorigenesis., with the overlapping functions suggesting potential links between stress response, autophagy and cancer therapy. 12 Regulation of autophagy is therefore a promising strategy to enhance anticancer drug effectiveness.

Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression

“…Previous reports indicated that antitumor drug administration results in an increase in HMOX1 expression in tumor cells, which might be a pro‐survival mechanism linked to the induction of autophagy . This suggests that autophagy is induced in tumor cells treated with antitumor drugs and is, thereby, involved in acquired resistance to chemotherapy …”

Functional role of TRP channels in modulating ER stress and Autophagy

“…In chaperone-mediated autophagy the substrates have a pentapeptide lysosome-targeting motif (KFERQ) that is recognized by a complex of chaperone proteins and target the complex to lysosomal membrane. Given that autophagy has been linked to inhibit several diseases, like neurodegeneration, diabetes and infectious diseases as well as promotion of some cancer especially chemoresistance (as reviewed in [28], [29] and [30]); the linkages between ER stress and autophagy may also have relevance to several of these diseases.…”

AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy

“…Autophagy plays a critical role in evolutionarily conserved cellular degradation process, providing materials and energy for cell metabolism under certain stress, such as oncogenic stress or cancer drug stress [11]. The role of autophagy in chemoresistance should be under intense investigation.…”