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Review
. 2021 Aug 16;26(16):4954.
doi: 10.3390/molecules26164954.

The Role of Autophagy in Anti-Cancer and Health Promoting Effects of Cordycepin

Affiliations
Review

The Role of Autophagy in Anti-Cancer and Health Promoting Effects of Cordycepin

Yu-Ying Chen et al. Molecules. .

Abstract

Cordycepin is an adenosine derivative isolated from Cordyceps sinensis, which has been used as an herbal complementary and alternative medicine with various biological activities. The general anti-cancer mechanisms of cordycepin are regulated by the adenosine A3 receptor, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), and glycogen synthase kinase (GSK)-3β, leading to cell cycle arrest or apoptosis. Notably, cordycepin also induces autophagy to trigger cell death, inhibits tumor metastasis, and modulates the immune system. Since the dysregulation of autophagy is associated with cancers and neuron, immune, and kidney diseases, cordycepin is considered an alternative treatment because of the involvement of cordycepin in autophagic signaling. However, the profound mechanism of autophagy induction by cordycepin has never been reviewed in detail. Therefore, in this article, we reviewed the anti-cancer and health-promoting effects of cordycepin in the neurons, kidneys, and the immune system through diverse mechanisms, including autophagy induction. We also suggest that formulation changes for cordycepin could enhance its bioactivity and bioavailability and lower its toxicity for future applications. A comprehensive understanding of the autophagy mechanism would provide novel mechanistic insight into the anti-cancer and health-promoting effects of cordycepin.

Keywords: anti-cancer; autophagy; cordycepin; health-promoting effects; immune systems; kidney; neuron.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The anti-cancer mechanisms of cordycepin-induced autophagy. Various stress conditions, such as metabolic starvation, hypoxia, and DNA damage, initiate the autophagic process. Stress conditions inhibit mechanistic target of rapamycin (mTOR), leading to the activation of Unc-51-like kinase 1 (ULK1) complex, which triggers the formation of the phagophore by activating the “initiation complex”. Cordycepin could cause DNA damage and trigger the inhibition of the mTOR pathway to induce cancer cell death. The phosphatidylethanolamine-conjugated form of Microtubule-associated protein 1A/1B-light chain 3-II (LC3-II), which is converted from LC3-I by ATG4-dependent cleavage, is critically involved in the fusion of mature autophagosomes and lysosomes. The autophagolysosome, which is already fused with a lysosome, could then result in the degradation and recycling of metabolites. Cordycepin also upregulates LC3-II expression, leading to autophagy in cancer cells.
Figure 2
Figure 2
The dual role of autophagy in kidney homeostasis and disease. Basal autophagy is a protective role in the maintenance of kidney homeostasis, structure, and functions. TOR–autophagy spatial coupling compartments (TASCCs), mTORC1 and AMPK are major pathways contributed to the maintenance of podocyte homeostasis. In tubular cells, autophagy prevents inflammation and fibrosis via downregulating NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation and ER stress. However, pathogenesis role of autophagy contributes to acute kidney injury, chronic kidney diseases and polycystic kidney diseases via WNT family member 1 (WNT1)-induced signaling pathway protein-1 (WISP-1), Myc, CCAAT-enhancer-binding protein (C/EBP) or protein kinase C alpha (PKCα). Meanwhile, autophagy dysfunction or over activation accompanied by other cell death modalities might induce tubular atrophy, promote kidney fibrosis, thereby, aggravate kidney diseases.
Figure 3
Figure 3
The role of autophagy in neurodegenerative diseases. The dysfunctions of autophagy are observed in neurodegenerative diseases, including AD, PD and HD, due to deficits of ATG family, Beclin-1, LC3, SQSTM1/p62, etc. Since the autophagy could not degrade disease-causing proteins properly, accumulations of Aβ plaques, Lewy bodies and HTT aggregates are detected in AD, PD and HD, respectively, finally leading to neurodegeneration.
Figure 4
Figure 4
The role of autophagy in immune systems. Autophagy and autophagy-associated proteins are required for pathogen clearance and antigen-presenting signaling in the immune system. LC3 takes part in the capacity to clear apoptotic cells and pathogens in innate immune responses. In the adaptive immune system, ATG5 involves in MHC class I and MHC class II antigen presentation in APCs leading to the T cell responses. Autophagy-associated proteins plays an important role in the innate and adaptive immune regulation.
Figure 5
Figure 5
The possible potential therapy of cordycepin for different human diseases. The major extract cordycepin from Cordyceps regulates different stages of autophagy homeostasis inside cells to reduce inflammation and oxidative stress, providing further evidence of its potential as a candidate for therapy for cancer, kidney, neuron, and immune diseases.

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