Search

Simple Summary: Beta-transducin repeat-containing proteins (β-TrCPs) are a component of the E3 ubiquitin ligase complex and function in many cellular processes to maintain protein homeostasis. Mounting evidence suggests that β-TrCPs are aberrantly upregulated in cancer tissues and are potential targets for cancer treatment. Although extensive studies have been performed to understand the mode of regulation of their substrates and its biological consequences, little attention has been paid to the mechanisms of the regulation of β-TrCPs themselves. The current review is focused on the modulation of β-TrCPs' activities and the implications for cancer treatment. Beta-transducin repeat-containing proteins (β-TrCPs) are E3-ubiquitin-ligase-recognizing substrates and regulate proteasomal degradation. The degradation of β-TrCPs' substrates is tightly controlled by various external and internal signaling and confers diverse cellular processes, including cell cycle progression, apoptosis, and DNA damage response. In addition, β-TrCPs function to regulate transcriptional activity and stabilize a set of substrates by distinct mechanisms. Despite the association of β-TrCPs with tumorigenesis and tumor progression, studies on the mechanisms of the regulation of β-TrCPs' activity have been limited. In this review, we studied publications on the regulation of β-TrCPs themselves and analyzed the knowledge gaps to understand and modulate β-TrCPs' activity in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma has a clear male predominance, but gender-specific differences remain incompletely understood. Our findings look specifically at the Louisiana population, which has some of the highest rates of hepatitis, alcoholic liver disease, and metabolic syndrome—thus providing important data to better evaluate HCC trends. Our findings help illustrate specific gender differences in this disease, which remains one of the leading causes of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a male-dominated disease. Currently, gender differences remain incompletely defined. Data from the state tumor registry were used to investigate differences in demographics, comorbidities, treatment patterns, and cancer-specific survival (HSS) among HCC patients according to gender. Additional analyses were performed to evaluate racial differences among women with HCC. 2627 patients with HCC were included; 498 (19%) were women. Women were mostly white (58%) or African American (39%)—only 3.8% were of another or unknown race. Women were older (65.1 vs. 61.3 years), more obese (33.7% vs. 24.2%), and diagnosed at an earlier stage (31.7% vs. 28.4%) than men. Women had a lower incidence of liver associated comorbidities (36.1% vs. 43%), and more often underwent liver-directed surgery (LDS; 27.5% vs. 22%). When controlling for LDS, no survival differences were observed between genders. African American women had similar HSS rates compared to white women (HR 1.14 (0.91,1.41), p = 0.239) despite having different residential and treatment geographical distributions. African American race and age >65 were predictive for worse HSS in men, but not in women. Overall, women with HCC undergo more treatment options—likely because of the earlier stage of the cancer and/or less severe underlying liver disease. However, when controlling for similar stages and treatments, HCC treatment outcomes were similar between men and women. African American race did not appear to influence outcomes among women with HCC as it did in men. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an aggressive and intractable malignancy. Although a high-level expression of epidermal growth factor receptor (EGFR) is a distinct feature of TNBC, targeting EGFR has not been successful yet. Here, we described a combination of the EGFR inhibitor gefitinib and IκB kinase (IKK) inhibitor IKK16 (Gefitinib+IKK16) as a potential therapeutic approach to treat TNBC. The combination of these drugs resulted in reduced cell viability and survival in TNBC cells in vitro. Mechanistically, several components of PI3K/AKT/mTOR pathway were further downregulated by drug combination compared with single-agent treatments. Gene expression analysis revealed that several NF-κB/RELA targets were suppressed, and a couple of tumor suppressor genes were induced by the drug combination. Taken together, targeting IKK may potentiate EGFR inhibition in TNBC. Triple-negative breast cancer (TNBC) remains as an intractable malignancy with limited therapeutic targets. High expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis of TNBC; however, EGFR targeting has failed with unfavorable clinical outcomes. Here, we performed a combinatorial screening of fifty-five protein kinase inhibitors with the EGFR inhibitor gefitinib in the TNBC cell line MDA-MB-231 and identified the IκB kinase (IKK) inhibitor IKK16 as a sensitizer of gefitinib. Cell viability and clonogenic survival assays were performed to evaluate the antiproliferative effects of the gefitinib and IKK16 (Gefitinib + IKK16) combination in TNBC cell lines. Western blot analyses were also performed to reveal the potential mode of action of this combination. In addition, next-generation sequencing (NGS) analysis was performed in Gefitinib+IKK16-treated cells. The Gefitinib+IKK16 treatment synergistically reduced cell viability and colony formation of TNBC cell lines such as HS578T, MDA-MB-231, and MDA-MB-468. This combination downregulated p-STAT3, p-AKT, p-mTOR, p-GSK3β, and p-RPS6. In addition, p-NF-κB and the total NF-κB were also regulated by this combination. Furthermore, NGS analysis revealed that NF-κB/RELA targets including CCL2, CXCL8, EDN1, IL-1β, IL-6, and SERPINE1 were further reduced and several potential tumor suppressors, such as FABP3, FADS2, FDFT1, SEMA6A, and PCK2, were synergistically induced by the Gefitinib-+IKK16 treatment. Taken together, we identified the IKK/NF-κB pathway as a potential target in combination of EGFR inhibition for treating TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is an intractable subset of breast cancer without an efficient therapeutic strategy due to the lack of tractable targets, such as the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Activation and/or amplification of epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK)/ extracellular signal-regulated kinase (ERK) pathways is known in TNBC; however, interventions for these targets have not been successful to date. To explore a combinatorial strategy with existing clinical/preclinical protein kinase inhibitors (PKIs) in TNBC cells, we performed a series of cytotoxicity (cell viability) screenings with various PKIs in the presence figure of an EGFR inhibitor, gefitinib. The dual inhibition of AKT and MEK with gefitinib reduced the proliferation and colony formation of TNBC cells by inducing apoptosis. Our finding suggests a new approach for treating TNBC with a multiplex combination of PKIs. There is an unmet medical need for the development of new targeted therapeutic strategies for triple-negative breast cancer (TNBC). With drug combination screenings, we found that the triple combination of the protein kinase inhibitors (PKIs) of the epidermal growth factor receptor (EGFR), v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK) is effective in inducing apoptosis in TNBC cells. A set of PKIs were first screened in combination with gefitinib in the TNBC cell line, MDA-MB-231. The AKT inhibitor, AT7867, was identified and further analyzed in two mesenchymal stem-like (MSL) subtype TNBC cells, MDA-MB-231 and HS578T. A combination of gefitinib and AT7867 reduced the proliferation and long-term survival of MSL TNBC cells. However, gefitinib and AT7867 induced the activation of the rat sarcoma (RAS)/ v-raf-1 murine leukemia viral oncogene homolog (RAF)/MEK/ extracellular signal-regulated kinase (ERK) pathway. To inhibit this pathway, MEK/ERK inhibitors were further screened in MDA-MB-231 cells in the presence of gefitinib and AT7867. As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells. [ABSTRACT FROM AUTHOR]

Lung cancer stem cells (CSCs) play a pivotal role in tumor development, drug resistance, metastasis and recurrence of lung cancer. Thus, it is of great importance to study the mechanism by which CSCs are regulated. In this study, we demonstrate that the deubiquitinase USP4 is critically important in promoting lung cancer stemness. Silencing of USP4 leads to reduction of Oct4 and Sox2 expression, decreased CD133+ cell population and inhibition of tumorsphere formation. Conversely, ectopic expression of USP4 significantly enhances lung cancer cell stemness, which is effectively rescued by simultaneous silencing of Twist1. Mechanistically, we identified USP4 as a novel deubiquitinase of Twist1. USP4 binds to, deubiquitinates and stabilizes Twist1 protein. Furthermore, we show that USP4 expression is elevated in human lung cancer specimens and is positively correlated with Twist1 expression. High expression of USP4/Twist1 is associated with poor clinical outcomes of lung cancer patients. Together, this study highlights an important role for USP4 in lung cancer stemness and suggests USP4 as a potential target for lung cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]