Abstract
Testicular cancer is the most commonly diagnosed cancer in men at 15‐44 years of age, and radical orchidectomy combined with chemotherapy is currently considered as the standard treatment. However, drugs resistance and side effects that impact the quality of life for patients with testicular cancer have not been markedly improved in recent decades. In this study, we characterized the pharmacological exacerbation of the unfolded protein response (UPR), which is an effective approach to kill testicular cancer cells, by carrying out a clustering analysis of mRNA expression profiles and the immunobloting examination of cordycepin‐treated MA‐10 cells. The UPR is executed in response to endoplasmic reticulum stress to complement by an apoptotic response if the defect cannot be resolved. Results showed that cordycepin significantly modulated FoxO/P15/P27, PERK‐eIF2α (apoptotic), and the IRE1‐XBP1 (adaptive) UPR pathways. Interestingly, a fraction of MA‐10 cells survived after cordycepin treatment, the AKT, LC3 I/II, and MAPK signaling pathways were highly induced in attached cells as compared to the suspended cells, illustrating the drug resistance to cordycepin via activating AKT and MAPK pathways in MA‐10 cells. In summary, PERK‐eIF2α signaling pathway is required for pro‐apoptotic UPR in MA‐10 cell death following cordycepin treatment, suggesting a potential therapeutic application in treating testicular cancer. However, activation of AKT and MAPK pathways could possibly result in drug resistance to cordycepin in MA‐10 cells.
Highlights
Expressions of apoptotic makers, cleaved caspase‐3 and PARP, were much lower in attachedMA‐10 cells as compared to the suspended cells (Figure 7A,B). These results demonstrated that pro‐survival AKT pathway and autophagy were activated, and pro‐apoptotic caspase pathway was reduced in attached MA‐10 cells, illustrating that drug resistance to cordycepin does exist in MA‐10 cells
We have previously published that cordycepin reduced cell viability and induced apoptosis through activating caspases, inducing cell cycle arrest, regulating p38 MAPKs signaling, increasing ROS levels, and suppressing PI3K/ AKT signaling in MA‐10 cells.[24]
We revealed that cordycepin could induce MA‐10 cell death by reducing FoxO/P15/P27/CDK4 pathways (Figure 3) to arrest cell cycle[24] and inducing endoplasmic reticulum (ER) stress to cause unfolded protein response (UPR)‐ dependent apoptosis through activating the PERK/eIF2α/ ATF3/CHOP and the inositol‐requiring enzyme 1 (IRE1)/XBP1 pathways
Summary
Testicular cancer, including germ cell, Sertoli cell, and Leydig cell tumors, is one of the most common solid tumors in men between 15 and 44 years of age with about 9310 new cases found in the United States annually.[1,2] Chemotherapy with or without surgery and/or radiotherapy combination is an important therapeutic strategy for testicular cancers.[3,4] the clinical applications of chemotherapy are limited because of severe side effects, such as cardiovascular diseases and respiratory infections, which lead to a 6% increased risks of noncancer death in long‐term testicular cancer survivors after treatments with chemotherapy and/or radiotherapy.[5,6] This necessitates. ATF6, after cleavage in the Golgi, translocates to the nucleus and activates the transcription of genes involved in protein folding, processing, and FIGURE 1 Gene ontology analysis for cordycepin regulated genes in MA‐10 cells. Microarray analysis of MA‐10 cell gene expression in response to 100 μmol/L cordycepin treatment for 3 h. Drug resistance has been demonstrated in numerous tumor treatments, and several different mechanisms have been investigated and revealed.[25] the possible mechanisms related to cordycepin‐induced drug resistance in MA‐10 cells remain elusive, which is investigated in this study
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