The efficacy and mechanism of proteasome inhibitors in solid tumor treatment

2021 ◽  
Vol 16 ◽  
Author(s):  
Lei Zhang ◽  
Mengyang Wu ◽  
Ruicong Su ◽  
Di Zhang ◽  
Guilian Yang
Keyword(s):  
Signaling Pathways ◽  
Solid Tumors ◽  
Combination Chemotherapy ◽  
Solid Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Anticancer Efficacy ◽  
Mesenchymal Transition

Background: The ubiquitin-proteasome system (UPS) is critical in cellular protein degradation and widely involved in the regulations of cancer hallmarks. Targeting the UPS pathway has emerged as a promising novel treatment in hematological malignancies and solid tumors. Objective: This review mainly focuses on the preclinical results of proteasome inhibitors in solid tumors. Methods: We analyzed the published articles associated with the anticancer results of proteasome inhibitors alone or combination chemotherapy in solid tumors. Important data presented in abstract form were also discussed in this review. Results/Conclusion: Proteasome inhibitors, such as bortezomib and carfilzomib, are highly effective in treating solid tumors. The anticancer efficacy is not limited to affect the proteasomal inhibition-associated signaling pathways but also widely involves the signaling pathways related to cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT). In addition, proteasome inhibitors overcome the conventional chemo-resistance of standard chemotherapeutics by inhibiting signaling pathways, such as NF-κB or PI3K/Akt. Combination chemotherapy of proteasome inhibitors and standard chemotherapeutics are widely investigated in multiple relapsed or chemo-resistant solid tumor types, such as breast cancer and pancreatic cancer. The proteasome inhibitors re-sensitize the standard chemotherapeutic regimens and induce synergistic anticancer effects. The development of novel proteasome inhibitors and delivery systems also improves the proteasome inhibitors’ anticancer efficacy in solid tumors. This review summarizes the current preclinical results of proteasome inhibitors in solid tumors and reveals the potential anticancer mechanisms.

scholarly journals Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jillian Hattaway Luttman ◽  
Ashley Colemon ◽  
Benjamin Mayro ◽  
Ann Marie Pendergast
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Abl Kinases ◽  
Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 348 ◽  
Author(s):  
Ravindran ◽  
Pasha ◽  
Agouni ◽  
Munusamy
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

scholarly journals Exosome-Derived LINC00960 and LINC02470 Promote the Epithelial-Mesenchymal Transition and Aggressiveness of Bladder Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1419
Author(s):  
Cheng-Shuo Huang ◽  
Jar-Yi Ho ◽  
Jung-Hwa Chiang ◽  
Cheng-Ping Yu ◽  
Dah-Shyong Yu
Keyword(s):  
Bladder Cancer ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition ◽  
Bladder Cancer Cells

Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.

scholarly journals MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1040 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Hui Li Ang ◽  
Ebrahim Rahmani Moghadam ◽  
Shima Mohammadi ◽  
Vahideh Zarrin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Therapy ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
The Impact

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process

Biochimie ◽  
2019 ◽  
Vol 165 ◽  
pp. 229-234 ◽  
Author(s):  
Mostafa Karimi Roshan ◽  
Arash Soltani ◽  
Anvar Soleimani ◽  
Kolsoum Rezaie Kahkhaie ◽  
Amir R. Afshari ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Mesenchymal Transition
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