Proteasome Activity In Cancer Cells Research Articles

α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1.

Proteasome inhibitors (PIs) have emerged as an attractive novel cancer therapy. However, most solid cancers are seemingly resistant to PIs. The activation of transcription factor Nuclear factor erythroid 2 related factor-1 (NFE2L1) has been characterized as a potential resistance response to protect and restore proteasome activity in cancer cells. In this study, we demonstrated that α-Tocotrienol (T3) and redox-silent analogs of vitamin E (TOS, T3E) enhanced the sensitivity of bortezomib (BTZ), a proteasome inhibitor, in solid cancers through modulation of NFE2L1. In BTZ treatment, all of T3, TOS, and T3E inhibited an increase in the protein levels of NFE2L1, the expression levels of proteasome-related proteins, as well as the recovery of proteasome activity. Moreover, the combination of one of T3, TOS, or T3E and BTZ induced a significant decrease in cell viability in solid cancer cell lines. These findings suggested that the inactivation of NFE2L1 by T3, TOS, and T3E is essential to potentiate the cytotoxic effect of the proteasome inhibitor, BTZ, in solid cancers.

NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression.

Proteasomes are protease complexes essential for cellular homeostasis, and their activity is crucial for cancer cell growth. However, the mechanism of how proteasome activity is maintained in cancer cells has remained unclear. The CNC family transcription factor NFE2L1 induces the expression of almost all proteasome-related genes under proteasome inhibition. Both NFE2L1 and its phylogenetically closest homolog, NFE2L3, are highly expressed in several types of cancer, such as colorectal cancer. Here, we demonstrate that NFE2L1 and NFE2L3 complementarily maintain basal proteasome activity in cancer cells. Double knockdown of NFE2L1 and NFE2L3 impaired basal proteasome activity in cancer cells and cancer cell resistance to a proteasome inhibitor anticancer drug, bortezomib, by significantly reducing the basal expression of seven proteasome-related genes: PSMB3, PSMB7, PSMC2, PSMD3, PSMG2, PSMG3, and POMP Interestingly, the molecular basis behind these cellular consequences was that NFE2L3 repressed NFE2L1 translation by the induction of the gene encoding the translational regulator CPEB3, which binds to the NFE2L1 3' untranslated region and decreases polysome formation on NFE2L1 mRNA. Consistent results were obtained from clinical analysis, wherein patients with cancer having tumors expressing higher levels of CPEB3/NFE2L3 exhibit poor prognosis. These results provide the novel regulatory mechanism of basal proteasome activity in cancer cells through an NFE2L3-CPEB3-NFE2L1 translational repression axis.

Reporter PET Images Bortezomib Treatment-Mediated Suppression of Cancer Cell Proteasome Activity

Proteasomal protein degradation is a promising target for cancer therapy. Here, we developed a positron emission tomography (PET) technique based on the sodium-iodide symporter (NIS) gene fused with the carboxyl-terminal of ornithine decarboxylase (cODC) that noninvasively images cancer cells with inhibited proteasome activity. A retroviral vector was constructed in which the murine cODC degron was fused to the human NIS gene (NIS-cODC). Transiently transduced CT26 and HT29 colon cancer cells and stably expressing CT26/NIS-cODC cells were prepared. In cancer cells transiently transduced with NIS-cODC, NIS expression and transport activity was low at baseline, but NIS protein and 125I uptake was significantly increased by inhibition of proteasome activity with bortezomib. Stable CT26/NIS-cODC cells also showed increased cytosolic and membrane NIS by bortezomib, and four different stable clones displayed bortezomib dose-dependent stimulation of 125I and 99mTc-04− uptake. Importantly, bortezomib dose-dependently suppressed survival of CT26/NIS-cODC clones in a manner that closely correlated to the magnitudes of 125I and 99mTc-04− uptake. CT26/NIS-cODC tumors of bortezomib-treated mice demonstrated greater 124I uptake on PET images and increased NIS expression on tissue staining compared to vehicle-injected animals. NIS-cODC PET imaging may allow noninvasive quantitative monitoring of proteasome activity in cancer cells treated with bortezomib.

Disulfiram's Anticancer Activity: Evidence and Mechanisms.

Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence indicates that DSF possesses a great potential for the treatment of human cancers. DSF's anticancer activity has been demonstrated in both in vitro and in vivo model systems, and has been tested in human clinical trials for various cancer types. It is also evident that DSF can sensitize tumor cells to radiotherapy and enhance the cytotoxicity of anticancer drugs, thus DSF may serve as an adjuvant therapy. The key to DSF's anticancer action relates to its ability to suppress cancer stem cells by targeting aldehyde dehydrogenase (ALDH), a marker of cancer stem cells, and inhibit proteasome activity in cancer cells by forming complexes with metal ions. In addition, DSF targets epigenetic mechanisms and modulates cellular signaling pathways to slow down tumor progression. DSF also induces apoptosis, inhibits cancer cell proliferation, and suppresses cancer cell metastasis. Considering that the pharmacokinetics of DSF are well-established and a safety profile has been recorded, this compound is an attractive "old" drug that has great potential for rapid development into a new cancer therapeutic. This article provides a brief review of the history of DSF use in humans, evidence for its anticancer activities, the molecular mechanisms of DSF action that have been illustrated by recent studies, and the potential for repurposing DSF as a new chemotherapeutic drug in the near future.

N-α-acetyltransferase 10 protein is a negative regulator of 28S proteasome through interaction with PA28β

N-α-acetyltransferase 10 protein (Naa10p) regulates various pathways associated with cancer cell proliferation, metastasis, apoptosis and autophagy. However, its role in protein quality control is unknown. Here, we report that Naa10p is physically associated with proteasome activator 28β (PA28β). Naa10p also interacts with PA28α in a PA28β-dependent manner. Naa10p negatively regulates PA28-dependent chymotrypsin-like proteasome activity in cancer cells and in a cell-free system reconstituted with purified proteins, which is not related to 26S proteasome. Acetyltransferase activity of Naa10p is not required for its effect on chymotrypsin-like proteasome activity. Therefore, our data reveal that Naa10p suppresses 28S proteasome activity through interaction with PA28β. Structured summary of protein interactionsNaa10pphysically interacts with PA28 alpha and PA28 beta by anti bait coimmunoprecipitation (View Interaction: 1, 2)

Defective accumulation of p53 protein in X-irradiated human tumor cells with low proteasome activity

Because the loss of p53 function is the most common event in human cancers, p53 gene therapy is now under clinical trial. Here, we examined whether X-irradiation potentiated the function of the exogenous p53 protein induced in H1299 cells and human non-small cell lung carcinoma cells. We found that the induced p53 protein was not accumulated after X-irradiation, although both phosphorylation of the p53 protein at Ser15 and Ser20, and phosphorylation of MDM2 were observed normally. Next, we examined the kinetics of degradation of the p53 protein in the presence of cycloheximide, a translation inhibitor. The level of the p53 protein in HE49 cells decreased rapidly, but there was no change in the H1299 cells. Furthermore, significant accumulation of the p53 protein was observed only in the HE49 cells after being treated for 2 h with ALLN, a proteasome inhibitor. These results indicate that low proteasome activity in H1299 cells cause defective accumulation of the p53 protein. Furthermore, it is possible that proteasome activity in cancer cells may determine the prognosis of the p53 gene therapy.