Mini-reviewTargeting apoptotic and autophagic pathways for cancer therapeutics
Introduction
Cancer, a disease results from mutation of oncogenes and/or tumor suppressor genes that can develop to the alteration of signaling pathways, including some pathways involved in cancer cell proliferation and/or attrition. Whereas, one of the most important process regulating the balance of cell growth and cell death is programmed cell death (PCD), evolutionarily-conserved processes to decide cell fate, and therefore PCD has been drawing rising attention in cancer treatment [1], [2]. There exist two forms of PCD, apoptosis and autophagy, and morphological differences are obvious between them. Apoptotic cell death (type I PCD) (from Greek ‘apo’, meaning from, and ‘ptosis’, meaning falling) is presented by shrinkage of cell, membrane blebbing and shattering that are phagocytosed by surrounding cells or phagocytes fall from the dying cell into apoptotic bodies [3]. Differs from apoptosis, autophagy, type II PCD (from Greek auto-oneself, phagy-to eat), is dependent on the presence of autophagosomes, autolysosomes, as well as an intact nucleus in the cell [4]. Also, many reports have demonstrated that autophagy is not only a survival response to either growth factor or nutrient deprivation but an important molecular mechanism for tumor cell suicide [5]. Although apoptosis and autophagy bear distinct morphological characteristics and physiological process, there still exists intricate collaboration between them. Sometimes apoptosis and autophagy could exert synergetic effect while sometimes autophagy would be triggered only when apoptosis is suppressed [6]. Moreover, recent studies have further pointed out that apoptosis and autophagy may be interconnected and even simultaneously regulated by the same trigger in tumor cells [7], [8], [9]. With the molecular mechanisms of apoptosis and autophagy and their intricate relationship are gradually investigated, numerous anti-tumor drugs targeting the signaling pathways implicated in these two types of PCD have been utilized on clinic.
In this review, we mainly focus on the advances of molecular mechanisms of apoptosis and autophagy and their cross-talks by referring to several key signaling pathways, and further sum up apoptosis- and autophagy-related anti-tumor drugs. Therefore, understanding the complex mechanisms of apoptosis and autophagy may help cancer biologists and clinicians to further harness programmed cell death (PCD) pathways as new drug targets for cancer therapy.
Section snippets
Core apoptosis-related signaling pathways in cancer
In the past decade, tremendous advance about cancer biology and cancer genetics has been realized, and the most important achievement is the realization of apoptosis and apoptosis-related proteins or genes which bear prominent effect on the malignant phynotype. And, it is widely demonstrated that some oncogenic mutations suppressing apoptosis may lead to tumor initiation, progression or metasis [10]. Therefore, more refined and effective researches are needed to uncover the molecular mechanisms
Core autophagy-related signaling pathways in cancer
The investigation of autophagy-related molecular mechanisms starts in 1993, however until 1999 the link between autophagy and tumor has been established, since the observation that the atg gene Beclin-1 inhibits tumorigenesis and is assumed to be a candidate tumor suppressor [46]. With the increasing number of atgs has been found to be oncogenes or tumor suppressors, their pro- or anti-autophagic roles have been gradually explored as well. Therefore, major autophagic regulators and the
The cross-talks between apoptosis and autophagy in cancer
As the critical strategies controlling cell fate, apoptosis and autophagy are crucial in normal physiology and pathology. In some specific cases, there might exist positive or negative link between apoptosis and autophagy, indicating the existence of ‘molecular switch’ between them. Recent studies have indicated that some important regulators can synchronously control apoptosis and autophagy despite of the remarkable differences between the two kinds of programmed cell deaths [83], [84]. And it
Targeting apoptotic and autophagic pathways in cancer therapeutics
Recently, many anti-tumor agents have been targeting the proteins involved in apoptosis while the effects of these agents might be various, and they either induce cancer cell death or enhance the sensitivity of cancer cells to certain cytotoxic drugs or radiation. Some novel agents such as Arsenic trioxide (targeting the PML-RARα in intrinsic pathway), Caspases activators (targeting the caspases), Bortezomib (targeting the 20S proteosome in Ubiquitin/Proteosome System) and Imatinib-mesylate
Concluding remarks
Cancer, an intricate disease results from mutation of oncogenes and/or tumor suppressor genes that can develop to the alteration of signaling pathways, and the big challenge lying in anti-cancer therapy is the uncertain and intricate molecular mechanisms involved in cancer. At present, common viewpoint has been accepted that apoptosis and autophagy, two types of PCD, can be utilized in tumor treatment due to their capabilities of regulating cancer cell death. Several essential signaling
Conflict of interest
We declare that none of the authors have a financial interest related to this work.
Acknowledgments
We are grateful to Qian Liu (National University of Singapore), Chun-yang Li (Sichuan University) and Dr. Yan Cheng (Pennsylvania State University) for their critical reviews on this manuscript. We also thank Ming-wei Min (University of Cambridge), Huai-long Xu (Sichuan University) and He-jiao Bian (Boston University) for their helpful assistance with this work. In addition, this review is partially based upon studies that were supported by grants from the National Natural Science Foundation of
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