Notably, it also controls cancer cell survival.
Depending on the cell type and the prevalence of Rho GTPase signaling, MLN treatment results in cell clustering or invasive cell scattering. Herein, we show that mechanical stress induced by MLN in cancer cells is an important determinant of the therapeutic outcome. The investigation of these adverse drug effects is essential for further development of neddylation inhibitors as anticancer therapeutics. In androgen-independent PC3 cells, MLN was shown to promote cell proliferation and tumor sphere formation and to accelerate cancer cell migration. Notably, in VCaP cells, MLN markedly stimulates the prometastatic Wnt/β-Cat–FoxO pathway. On the other hand, we have shown that in VCaP cells bearing amplified copies of the AR gene, MLN could stimulate AR transcription and promote cell survival, particularly upon androgen depletion. A recent study suggested that MLN could also suppress prostate cancer (PCa) cells specifically by shutting down the transcription of the androgen receptor (AR) and its downstream targets. In various types of cancer cells, including prostate cancer, MLN induces self-inflicted DNA damage via re-replication, cell cycle arrest and apoptosis. The current understanding is that similar to clinically approved proteasome inhibitors, MLN exerts its anticancer activity by stabilizing a number of tumor suppressors and blocking several oncogenic pathways. This, in turn, prevents the degradation of approximately one-third of the human proteome, which depends on the activity of Nedd8-dependent ubiquitin ligases, of which cullin-RING E3 ligases (CRLs) are the main class. MLN specifically inhibits Nedd8-activating enzyme (NAE1) and, as a result, blocks neddylation of cellular proteins. There are currently 40 (including 14 in solid tumors) phase I-III clinical studies of pevonedistat listed on. In this work, we studied the effects of the preclinical drug MLN4924 (International Nonproprietary Name: Pevonedistat hereafter called “MLN”) in prostate cancer cells. As a result, chemotherapies fail to prevent metastasis and can even promote cancer cell dissemination by selecting treatment-resistant aggressive phenotypes.
This is a result of the relative inefficacy of the current drug discovery strategy that selects compounds mainly for their antiproliferative potencies and abilities to reduce the size of a primary tumor (response evaluation criteria in solid tumors, RECIST). The recurrence of treatment-resistant metastatic diseases is responsible for most cancer-related deaths.
Our finding that MLN4924 acts as a mechanotherapeutic opens new ways to improve the efficacy of neddylation inhibition as an anticancer approach. We identified complementary targets and drugs that allow for the induction of TJSR without stimulating RhoC. On the other hand, in PC3 cells that underwent partial epithelial-to-mesenchymal transition (EMT), the stimulation of RhoC induces an adverse effect by promoting amoeboid cell scattering and invasion. Notably, TJSR is a major cause of drug-induced apoptosis in these cells. This “tight junction stress response” (TJSR) causes the collapse of cell monolayers and a characteristic rupture of cancer spheroids. In LNCaP and VCaP cells, the stimulation of RhoA and RhoB by MLN4924 markedly upregulates the level of tight junction proteins at cell–cell contacts, which augments the mechanical strain induced by Rho signaling. The latter depends on the cell type and involves distinct Rho isoforms. We show that mechanical stress induced by MLN4924 in prostate cancer cells significantly affects the therapeutic outcome. Using focused protein profiling, drug and RNAi screening, we analyzed cellular pathways activated by neddylation inhibition. Here, we studied the effects of MLN4924 on cell growth, migration and invasion in cultured prostate cancer cells and in disease-relevant prostate tumoroids. However, despite being effective against hematologic malignancies, its success in solid tumors, where cell–cell and cell-ECM interactions play essential roles, remains elusive. The inhibition of neddylation by the preclinical drug MLN4924 represents a new strategy to combat cancer.
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