Abstract
BackgroundTNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment.MethodsDifferent inhibitors were used to study the cell death manner of DMOCPTL. RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4.ResultsDMOCPTL, a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13, the prodrug of DMOCPTL, effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed.ConclusionsThese findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.
Highlights
Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy [1]
The number of colonies was 82.7 ± 5.5, 71.5 ± 1.5 and 0 after treatment with vehicle, PTL or DMOCPTL at the same concentration of 0.5 μM. These results indicated that DMOCPTL could significantly inhibit colony formation of triple-negative breast cancer (TNBC) cells
We identify a derivative of PTL, DMOCPTL, as a potential anti-TNBC agent, which can induce ferroptosis and apoptosis through ubiquitination of GPX4. This is the first report of inducing ferroptosis through ubiquitination of GPX4 by binding to GPX4 directly
Summary
Ferroptosis is a new form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy [1]. Emerging evidence indicated that ferroptosis may have a tumor-suppressor function for cancer therapy. Small molecule ferroptosis inducers had a strong inhibition of tumor growth and enhanced the sensitivity of chemotherapeutic drugs [6]. Combination of chemotherapeutic drugs such as tmozolomide, cisplatin, doxorubicin with ferroptosis inducer erastin resulted in a remarkable synergistic effect on tumor treatment [3]. Induction of ferroptosis has become a novel potential therapeutic strategy for cancer therapy [7,8,9,10,11,12]. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
