Abstract
The MDM2 and MDMX oncogenes are overexpressed in various types of human cancer and are highly associated with the initiation, progression, metastasis and chemotherapeutic resistance of these diseases, including prostate cancer. The present study was designed to test a natural MDM2 inhibitor, Inulanolide A (InuA), for anti-prostate cancer activity and to determine the underlying mechanism(s) of action. InuA directly bound to the RING domains of both MDM2 and MDMX with high affinity and specificity and disrupted MDM2-MDMX binding, markedly enhancing MDM2 protein degradation. We further discovered that InuA bound to the DNA binding domain of NFAT1, resulting in marked inhibition of MDM2 transcription. InuA inhibited the proliferation, migration, and invasion of prostate cancer cells, regardless of their p53 status and AR responsiveness. Double knockdown of MDM2 and NFAT1 also revealed that the expression of both of these molecules is important for InuA’s inhibitory effects on the proliferation and invasion of prostate cancer cells. In summary, InuA represents a novel class of bifunctional MDM2 inhibitors, and should be further investigated as a candidate lead compound for prostate cancer prevention and therapy.
Highlights
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancerrelated death among men in the United States (Yap et al, 2016)
Novel approaches for inhibiting the murine double minute (MDM) oncoproteins, MDM2 and MDMX, are worthy of investigation and might be used clinically for the prevention and treatment of human prostate cancer, especially castration-resistant prostate cancer (CRPC)
We have shown that Inulanolide A (InuA) exerts robust inhibitory effects on the proliferation, migration, and invasion of prostate cancer cells, as well as on the protein expression of MDM2 and MDMX, in a p53- and androgen-independent manner
Summary
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancerrelated death among men in the United States (Yap et al, 2016). The androgen receptor (AR) is highly expressed in primary and metastatic prostate cancer and regulates multiple cellular functions, including proliferation, apoptosis, migration, invasion, and differentiation in all stages of prostate cancer (Spratt et al, 2016; Leach and Buchanan, 2017). Pharmacological inhibition of AR signaling represents a compelling and conventional therapeutic strategy for prostate cancer, which leads to a >90% 10-year survival of patients with low-risk, localized prostate cancer (Spratt et al, 2016; Leach and Buchanan, 2017). The benefits obtained with androgen deprivation therapy (ADT) for patients with CRPC. Targeting the NFAT1-MDM2-MDMX Network for Cancer Therapy are unacceptably low (Yap et al, 2016). Novel therapeutic and preventive approaches for prostate cancer are needed
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