Alternol can trigger cell cycle arrest and apoptosis as well as block proliferation and the epithelial-to-mesenchymal transition in tumor cells ( Tang et al., 2014). monosporus, which was obtained from the bark of yew trees in Kunming, southwest of China ( Liu et al., 2007). Accordingly, agents that inhibit such antiapoptotic proteins and/or upregulate proapoptotic proteins can potentially sensitize carcinoma cells to TRAIL-induced apoptosis ( Prasad et al., 2014).Īlternol is a novel compound purified from the fermentation product of the novel microorganism mutant strain Alternaria alternata var. IAP-1 and IAP-2 trigger RIP1 ubiquitination at the DR complex level, thereby interfering with apoptosis initiation ( Mahoney et al., 2008). FLIP functions as a caspase-8 inhibitor, whereas XIAP directly binds to caspase-9 and -3 to inhibit their activation ( Ashkenazi, 2008). Moreover, cellular FLICE-inhibiting protein (FLIP) and IAP family members, such as XIAP, IAP-1, and IAP-2, also affect TRAIL-induced apoptosis. In cells, the process of TRAIL-induced apoptosis is regulated by various intracellular mechanisms in addition to the DR expression levels, such as the expression of Bcl-2 family members, which can be further divided into proapoptotic and antiapoptotic members. Given that many human carcinoma cells evade TRAIL-induced apoptosis, unveiling and overcoming the mechanisms behind this resistance are necessary. The autocatalytic processing of procaspase-8 into caspase-8 within the DISC leads to the subsequent downstream activation of the executioner caspase-3. After binding to DR4 and/or DR5, TRAIL recruits Fas-associated death domain (FADD) and procaspase-8 into a death-inducing signaling complex (DISC) ( Lemke et al., 2014). Other TRAIL receptors, such as decoy receptor-1 and -2 (DcR1 and DcR2) and osteoprotegerin (OPG), exhibit dominant negative effects through competing with DR4 and DR5 for TRAIL binding ( Mahalingam et al., 2009). Among them, death receptor (DR) 4 (DR4, TRAIL-R1) and DR5 (TRAIL-R2) are functional receptors. Currently, five different TRAIL receptors have been identified. TRAIL is a promising antitumor agent, given that it selectively induces apoptosis in tumor cells while sparing normal cells ( Ashkenazi, 2015). Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the TNF super family. Removing ROS inhibited the induction of DR5 and blocked the antiapoptotic proteins induced by alternol.Ĭonclusion: Taken together, our research suggested that alternol increased TRAIL-mediated apoptosis via inhibiting antiapoptotic proteins and upregulating DR5 levels via ROS generation and the CHOP pathway. DR5 upregulation induced by alternol required the production of reactive oxygen species (ROS). Moreover, alternol increased the level of CHOP, which is necessary for the enhancing effect of alternol on TRAIL-induced apoptosis, given that downregulation of CHOP abrogated the synergistic effect. Alternol reduced the expression of antiapoptotic proteins and increased the levels of proapoptotic proteins. DR5 knockdown by siRNA eliminated the enhanced effect of alternol on TRAIL-mediated apoptosis. Results: When the mechanisms were investigated, we discovered that alternol increased DR5 expression. A xenogeneic tumor transplantation model was used to evaluate the anticancer effects of alternol/TRAIL in vivo. Luciferase assay was used to investigate whether CHOP regulated the expression of death receptor (DR) 5 through transcription. Real-time PCR and western blot were used to test the levels of mRNA and protein, respectively. Apoptosis was probed using the PI/annexin V method. Materials and Methods: Cytotoxic activity was measured by MTT assay. In our research, we discovered that alternol can sensitize TRAIL-induced apoptosis in renal carcinoma cells (RCCs).
Alternol is a new compound isolated from microbial fermentation that possesses antitumor activity in different tumors. However, the application of TRAIL-based antitumor therapies has been hindered due to drug resistance. Purpose: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a member of the TNF family, can selectively induce cancer cell death while sparing normal cells.
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