MitoCur-1 induces ferroptosis to reverse vemurafenib resistance in melanoma through inhibition of USP14

by Selleckchem | Jan 16 2024

Melanoma is an aggressive malignant tumor with a poor prognosis. Vemurafenib (PLX4032, vem) is applied to specifically treat BRAF V600E-mutated melanoma patients. However, prolonged usage of vem makes patients resistant to the drug and finally leads to clinical failure. We previously tested the combination regimen of tubulin inhibitor VERU-111 with vem, as well as USP14 selective inhibitor b-AP15 in combination with vem, both of which have showed profound therapeutic effects in overcoming vem resistance in vitro and in vivo. Most importantly, we discovered that vem-resistant melanoma cell lines highly expressed E3 ligase SKP2 and DUB enzyme USP14, and we have demonstrated that USP14 directly interacts and stabilizes SKP2, which contributes to vem resistance. These works give us a clue that USP14 might be a promising target to overcome vem resistance in melanoma. MitoCur-1 is a curcumin derivative, which was originally designed to specifically target tumor mitochondria inducing redox imbalance, thereby promoting tumor cell death. In this study, we have demonstrated that it can work as a novel USP14 inhibitor, and thus bears great potential in providing an anti-tumor effect and sensitizing vem-resistant cells by inducing ferroptosis in melanoma. Application of MitoCur-1 dramatically induces USP14 inhibition and inactivation of GPX4 enzyme, meanwhile, increases the depletion of GSH and decreases SLC7A11 expression level. As a result, ferrous iron-dependent lipid ROS accumulated in the cell, inducing ferroptosis, thus sensitizes the vem-resistant melanoma cell. Interestingly, overexpression of USP14 antagonized all the ferroptosis cascade events induced by MitoCur-1, therefore, we conclude that MitoCur-1 induces ferroptosis through inhibition of USP14. We believe that by inhibition of USP14, vem resistance can be reversed and will finally benefit melanoma patients in future.

Comments:

Your study sounds incredibly promising in tackling the challenge of vemurafenib resistance in melanoma. The identification of USP14 as a potential target and the development of MitoCur-1 as a USP14 inhibitor that induces ferroptosis seem like groundbreaking advancements.

By demonstrating the role of USP14 in stabilizing SKP2 and contributing to vemurafenib resistance, and further showing how MitoCur-1 inhibits USP14 to induce ferroptosis and sensitize vem-resistant melanoma cells, you've not only highlighted a potential solution for overcoming drug resistance but also provided a pathway to enhance the effectiveness of current treatments.

The ability of MitoCur-1 to induce ferroptosis by inhibiting USP14 and subsequently affecting GPX4, GSH depletion, and SLC7A11 expression is a significant finding. This could pave the way for novel therapeutic approaches that leverage ferroptosis as a means to combat drug-resistant melanoma.

Your work has strong implications for the future treatment of melanoma patients by potentially reversing vemurafenib resistance through USP14 inhibition and fostering a more effective therapeutic strategy. It's exciting to see such innovative approaches being explored to improve outcomes in cancer treatment.