Parthanatos and its associated components: Promising therapeutic targets for cancer
Graphical abstract
Introduction
An organism's biological homeostasis depends on the balance between cell proliferation and death. Cell death has traditionally been categorized into type I (apoptosis), type II (autophagy), and type III (necrosis), as first introduced by Schweichel and Merker [1]. Apoptosis is a cell death pathway that is caspase-dependent, and was considered the sole type of programmed cell death related to cell development and tissue remodeling [2]. Necrosis, on the other hand, has previously been thought to be an accidental mode of cell death in response to physicochemical traumas [3]. In recent decades, several novel forms of non-apoptotic programmed cell deaths (e.g., necroptosis, pyroptosis, parthanatos, ferroptosis, NETosis and pyronecrosis) have attracted increased attention [[4], [5], [6]]. Among all of these, parthanatos, a poly(ADP-ribose) (PAR) polymerase 1 (PARP1)-dependent form of non-apoptotic cell death, has been identified as a new target for disease therapy [7,8]. Under pathophysiologic situations, PARP1 over-activation, which is typically induced by DNA damage, causes the accumulation of PAR polymers and nuclear translocation of apoptosis inducing factor (AIF), all of which ultimately trigger parthanatos [9]. Parthanatos is involved in multiple critical pathological processes, including ischemia-reperfusion injury after brain ischemia or myocardial infarction [[10], [11], [12]], septic shock [13], and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease [14].
Malignant tumors, which are characterized by the risk of recurrence and drug resistance, are a major cause of mortality worldwide. Therefore, there is a significant need for the development of better therapeutic strategies. Increasing lines of evidence implicate that parthanatos is involved in the regulation of cancer cells [7,8,15]. Therefore, elucidation of the parthanatos pathway will contribute to a better understanding of tumorigenesis and potential novel anti-cancer therapeutics. In this review, we will summarize the molecular mechanisms of parthanatos pathway and functions of the components of parthanatos in tumorigenesis, as well as their huge promise in therapeutic application.
Section snippets
Overviews of parthanatos
Considering the significance of parthanatos in emerging cancer literature, a better understanding of the molecular mechanisms that underlie parthanatos signaling will likely have important implications for developing parthanatos-targeted therapy in cancer management. In principle, a multitude of different stimuli can initiate parthanatos, which mainly comprises of three phases of signal transduction, including the activation of PARP1, the translocation of AIF, and the resulting DNA
Functions of the components of parthanatos pathway in tumorigenesis
Multiple molecules that function in PARP1-dependent parthanatos cascade have been shown to be involved in tumorigenesis in a variety of ways and at individual steps (Fig. 2). Here, we summarize the possible mechanism of parthanatos-associated molecules in tumorigenesis.
Parthanatos and its associated components in cancer therapy
As already mentioned, parthanatos functions in a multistep fashion and plays a pleiotropic role in the tumorigenesis. Hence, targeting a number of steps in the cascade could serve as a promising therapeutic strategy in cancer management. We have summarized some representative agents of the parthanatos-associated components targeted therapy in Table 1. Additionally, it should be emphasized that cell death in a particular context displays features of more than a single form of cell death, but in
Conclusion and prospect
Parthanatos specifically depends on PARP1 hyperactivation and is independent of caspase. Canonical parthanatos mainly involves rapid PARP-1 activation, early PAR accumulation, cellular NAD+ and ATP depletion, mitochondrial depolarization, AIF release from the mitochondria, MIF recruitment, nuclear translocation of AIF/MIF complex, and ultimately DNA fragmentation. On the other hand, non-canonical parthanatos appears to function via an AIF-independent pathway, which reflects the complexity of
Authors’ contributions
YXZ, LHL and AWS participated in the design of the review. LHL, YXZ, SFT and YHY drafted the manuscript and made the original figures. YXZ, LHL and YLW critically revised the texts and figures. YCD, AWS and QCW supervised the research, led the discussion. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable
Funding
This work was funded by National Natural Science Foundation of China (81701144).
Availability of data and materials
Not applicable.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Acknowledgements
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These authors contributed equally to this manuscript.