Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy (original) (raw)
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Apoptosis and Autophagy: Therapeutic Implications in Cancer
International Journal of Experimental Research and Review, 2024
Despite the advances in the medical field so far, cancer remains a global health priority even now. Considering the drug resistance and the failure of cancer therapies to achieve complete eradication of cancer cells in certain populations, developing molecules that induce programmed cell death or apoptosis has been the focus of cancer research for several decades. Apoptosis evasion is one of the hallmarks of cancer cells, and efforts continue to achieve complete annihilation of cancer cells through selective killing. On the other hand, autophagy, a mode of cell degradation, is considered a double-edged sword. Recent studies show that autophagy also can be manipulated to selectively target cancer cells based on the tumor microenvironment and cellular context. Studies show that autophagy is an evolutionarily conserved process initiated during stress response and has enormous importance in maintaining physiological balance. Most importantly, the dynamic equilibrium between apoptosis and autophagy is crucial in maintaining cellular homeostasis. Although a ‘cell eating’ process, the fate of autophagic cells depends entirely on the nature of stress and the extent of crosstalk between autophagy. This understanding is of immense significance when designing therapeutic interventions targeting apoptosis and autophagy. Currently, several studies are ongoing to gain insights into the role of autophagy in cancer initiation, invasion, progression, angiogenesis, and metastasis. This review focuses on the two major cell death mechanisms, apoptosis and autophagy, in the context of cancer, their crosstalk, and the therapeutic interventions targeting both modes of cell death.
Frontiers in Oncology, 2011
Autophagy, a highly regulated cell "self-eating" pathway, is controlled by the action of over 34 autophagy-related proteins (collectively termed Atgs). Although they are fundamentally different processes, autophagy and apoptosis (type I programmed cell death), under certain circumstances, can be regulated by common signaling mediators. Current cancer therapies including chemotherapy and ionizing radiation are known to induce autophagy within tumor cells. However, autophagy plays a dual role of either pro-cell survival or pro-cell death in response to these cancer treatments, depending on the cellular context and the nature of the treatment. We review the current basic and translational cancer research literature on how autophagy impacts tumor cell survival ("to live") and death ("not to live") following treatment as well as the role of chemical mediators of autophagy.
Cytotoxic Autophagy in Cancer Therapy
International Journal of Molecular Sciences, 2014
Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.
Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy
Oncogene, 2015
Autophagy is a tightly-regulated catabolic process of cellular self-digestion by which cellular components are targeted to lysosomes for their degradation. Key functions of autophagy are to provide energy and metabolic precursors under conditions of starvation and to alleviate stress by removal of damaged proteins and organelles, which are deleterious for cell survival. Therefore, autophagy appears to serve as a pro-survival stress response in most settings. However, the role of autophagy in modulating cell death is highly dependent on the cellular context and its extent. There is an increasing evidence for cell death by autophagy, in particular in developmental cell death in lower organisms and in autophagic cancer cell death induced by novel cancer drugs. The death-promoting and -executing mechanisms involved in the different paradigms of autophagic cell death (ACD) are very diverse and complex, but a draft scenario of the key molecular targets involved in ACD is beginning to emer...
An overview on the role of autophagy in cancer therapy
Hematology & Medical Oncology, 2017
Autophagy is a highly regulated catabolic process through which cells recycle their own constituents by delivering them into lysosomes. Several studies have demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles in cells. In cancer, autophagy has been described to have paradoxical roles, acting both as tumor suppressor and as tumor promoter. In particular, it may exert different functions in response to cancer therapy, causing cancer resistance or increasing sensitivity to chemotherapeutic drugs and radiation. Therefore, autophagy could provide new means for the enhancement of antitumor drugs and radiation effectiveness.
Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy
Cancers
Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.
Autophagy in Cancer Cell Death
Biology, 2019
Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.
Chemico-Biological Interactions, 2013
Autophagy is a mechanism of protection against various forms of human diseases, such as cancer, in which autophagy seems to have an extremely complex role. In cancer, there is evidence that autophagy may be oncogenic in some contexts, whereas in others it clearly contributes to tumor suppression. In addition, studies have demonstrated the existence of a complex relationship between autophagy and cell death, determining whether a cell will live or die in response to anticancer therapies. Nevertheless, we still need to complete the autophagy-apoptosis puzzle in the tumor context to better address appropriate chemotherapy protocols with autophagy modulators. Generally, tumor cell resistance to anticancer induced-apoptosis can be overcome by autophagy inhibition. However, when an extensive autophagic stimulus is activated, autophagic cell death is observed. In this review, we discuss some details of autophagy and its relationship with tumor progression or suppression, as well as role of autophagy-apoptosis in cancer treatments.
A Summary of Autophagy Mechanisms in Cancer Cells
Rovedar , 2022
Autophagy is a well-known vital process in cells and plays a significant role in biological evolution, the immune system, and cell death. It can be effective in fatal disorders, such as nervous system degeneration, autoimmune diseases, and cancer. Autophagy has a dual role; on the one hand, it increases cell survival, and on the other hand, it causes cell death in advanced stages although no agreement has yet been accomplished on the role of autophagy in cellular processes. There is evidence that autophagic signaling regulation is inversely related to oncogenic signaling. Numerous commonly activated oncogenes (class I PtdIns3K, Akt, TOR, Bcl-2) inhibit autophagy, while commonly mutated or epigenetically silenced tumor suppressor genes (p53, PTEN, TSC1/TSC2) promote autophagy. Autophagy promotes cancer progression by supplying sufficient nutrients that enable cancer cell growth. FIP200, a related- autophagy protein, interacts with ATG 13 and induces autophagy. Increased autophagy causes the interaction of Becklin 118 with HER2, resulting in an increase in tumorigenesis. In order to make complete use of the autophagic properties in cancer treatment, further studies on its role in disease in the different biologics fields are essential. Cancer stem cells (CSCs) can regenerate, cause cancer, and enhance resistance to treatment, metastasis, and recurrence. Autophagy moderates stressful conditions and promotes resistance to anticancer therapy. In addition, autophagy regulates the ability of radiation in CSCs and leads to failure in anticancer therapies. Hence, autophagy is a potential therapeutic target for metastasis resistance and anticancer therapy recurrence. Regulation of autophagy using autophagy modulators alone does not improve the therapeutic effects of anticancer reagents. In contrast, it has supplied nutrients for cancer cells. Consequently, clinical trials aiming for autophagy through a combination of autophagy modulations and anticancer reagents are crucial to consider autophagy as a potentially effective therapeutic strategy in anticancer therapy.
Autophagy and Cancer Treatment Review
2021
Autophagy is a catabolic process that targets impaired organelles and proteins for lysosomal degradation to maintain cell hemostasis. Autophagy in cancer is dynamic and, more specifically, depending on the stage and type of tumor. Researches in genetically engineered mouse models are agreed with the concept that autophagy can constrain initiation of the tumor by controlling oxidative stress and DNA damage, while in established tumors, autophagy can also be required for tumor survival. As shown in preclinical models, suppression of autophagy restored chemotherapy sensitivity against tumor cells. Targeting autophagy in cancer will develop a new era for anti-cancer drugs, but more specific and potent inhibitors of autophagy are needed. The role of autophagy in cancer cells continues to emerge, and further studying to identify optimum strategies to modulate autophagy for therapeutic advantage.