VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

Bastola, Prabhakar; Neums, Lisa; Schoenen, Frank J.; Chien, Jeremy

doi:10.1016/j.molonc.2016.09.005

Cited by 74 publications

(81 citation statements)

References 60 publications

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“…Bastola et al described the preclinical activity of VCP inhibitors in ovarian cancer cells, and final outcomes showed that VCP inhibitors were able to induce ER stress, cause cell cycle arrest, and trigger caspase‐mediated cell death. Thus, VCP inhibitor can be used as a single agent or combined with other antitumor compounds …”

Section: Discussionmentioning

confidence: 99%

“…Among these specific inhibitors, NMS‐873 was initially developed as an allosteric, non‐ATP‐competitive, and potent noncovalent VCP inhibitor that impairs the ERAD pathway, activates the unfolded protein response (UPR), and induces apoptosis . In addition, other findings have revealed VCP as a potential target and inhibiting VCP has been associated with improved antitumor activity in vitro and in vivo . To date, the role of VCP in enhancing tumor radiation sensitivity has not been characterized in ESCC cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

et al. 2019

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Overcoming resistance to radiation is a great challenge in cancer therapy. Here, we highlight that targeting valosin‐containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy. Esophageal squamous cell carcinoma cell lines with high VCP expression were treated with VCP inhibitor combined with radiotherapy. Cell proliferation, colony formation, cell death, and endoplasmic reticulum (ER) stress signaling were evaluated. Moreover, patients with newly diagnosed locally advanced ESCC who were treated with radiotherapy were analyzed. Immunohistochemistry was used to detect the expression of VCP. The correlation between overall survival and VCP was investigated. Esophageal squamous cell carcinoma cells treated with VCP inhibitor and radiotherapy showed attenuated cell proliferation and colony formation and enhanced apoptosis. Further investigation showed this combined strategy activated the ER stress signaling involved in unfolded protein response, and inhibited the ER‐associated degradation (ERAD) pathway. Clinical analysis revealed a significant survival benefit in the low VCP expression group. Targeting VCP resulted in antitumor activity and enhanced the efficacy of radiation therapy in ESCC cells in vitro. Valosin‐containing protein is a promising and novel target. In patients with locally advanced ESCC who received radiotherapy, VCP can be considered as a useful prognostic indicator of overall survival. Valosin‐containing protein inhibitors could be developed for use as effective cancer therapies, in combination with radiation therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

et al. 2019

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“…Among the altered proteins, valosin‐containing protein (VCP) is a member of the AAA ATPases was identified as overexpressed protein which formed a central node in protein network analysis. Elevated VCP expression show positive correlation with progression, metastatic potential of Non‐small cell lung cancer (NSCLC), Ovarian, Colorectal cancer, and Osteosarcoma (Bastola, Neums, Schoenen, & Chien, ; Fu et al, ; Long, Zhang, Liu, Huang, & Luo, ; Valle et al, ). Furthermore, it has been reported that elevated VCP expression would lead to the poor prognosis of PCa (Tsujimoto et al, ).…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐6 induced overexpression of valosin‐containing protein (VCP)/p97 is associated with androgen‐independent prostate cancer (AIPC) progression

Duscharla

Reddy

Dasari

et al. 2018

Journal Cellular Physiology

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Though Androgen deprivation therapy (ADT) is effective initially, numerous patients become resistant to it and develop castration resistant PCa (CRPC). Cytokines promotes ligand independent activation of AR. Interleukin-6 (IL-6) levels are elevated in CRPC patients and regulate AR activity. However, progression to CRPC is not fully understood. In this study, we analyzed differential protein expression in LNCaP cells treated with IL-6 using proteomics. Results revealed altered expression of 27 proteins and Valosin-containing protein (VCP)/p97 plays a predominant role in co-regulation of altered proteins. Interestingly, IL-6 induced VCP expression through Pim-1 via STAT3 is AR independent there by suggesting a role for VCP in CRPC. Transfection of LNCaP cells for VCP overexpression showed an increased cell proliferation, migration, and invasion where as its inhibition by NMS-873 showed the reverse effect causing cell death. Mechanistic studies demonstrate that cell death occurs due to apoptosis by endoplasmic reticulum (ER) stress, elevated cell cycle inhibitors p21, p27kip1, and active PARP and reduced Bcl-2. VCP promotes cell invasion and migration by altering E-cadherin and Vimentin levels inversely triggering EMT of PCa cells. VCP immunostaining revealed no staining in BPH but strong staining in PCa. This study determines VCP may play an important role in progression to CRPC and it can be a favorable target with to develop new therapies to treat ADT resistant prostate cancer.

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“…Moreover, ER stress marker levels were increased in Bap31 knockout mice after tunicamycin injection compared with those in control mice [35]. The depletion of VCP by siRNA induces ER stress and the unfolded protein response (UPR) [36]. In addition, the C-terminus of Bap31 can be cleaved by caspase 8 to generate p20, which participates in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

B-Cell Receptor-Associated Protein 31 Regulates the Expression of Valosin-Containing Protein Through Elf2

Jia

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: B-cell receptor-associated protein 31 (Bap31) is an evolutionarily conserved, ubiquitously expressed, polytopic integral membrane protein in the endoplasmic reticulum (ER) that is involved in the regulation of apoptosis, protein transport and degradation. Patients with Bap31 mutations exhibit symptoms similar to those exhibited by patients with central nervous system (CNS) diseases, such as deafness, dystonia, and intellectual disability. The present study aimed to investigate the function of Bap31 in CNS diseases by identifying a CNS disease-related gene regulated by Bap31 and exploring the underlying molecular mechanism. Methods: ShRNA-Bap31 and siRNA-Bap31 were used to knockdown Bap31 in N₂a cells, and real-time PCR was performed to detect the mRNA levels of genes involved in CNS diseases. Western blot analyses were used to examine the protein levels of the candidate gene (valosin-containing protein, VCP) both in vivo and in vitro. The functions of Bap31 and VCP in mediating the degradation of the hyper-unstable mutant of cystic fibrosis trans-membrane conductance regulator (CFTRΔF508) were studied. Moreover, real-time PCR, Western blot and dual luciferase reporter analyses were conducted to investigate the molecular mechanism by which Bap31 regulates the expression levels of VCP. Results: VCP was identified as a candidate gene based on its differential expression in N₂a cells following both shRNA- and siRNA-mediated knockdown of Bap31. Both the mRNA and protein levels of VCP were regulated by Bap31 in vivo and in vitro. In the ER-associated degradation (ERAD) pathway, Bap31 also regulated VCP expression and caused differences in the binding quantities of CFTRΔF508 and VCP. Furthermore, a transcription factor of VCP (E74-like factor 2, Elf2) was regulated by Bap31, and Elf2 mediated the changes in VCP transcription and expression in cells with altered Bap31 expression. Conclusion: These results indicate that Bap31 regulates the expression of VCP possibly via Elf2 and support the potential molecular function of Bap31 in CNS diseases.

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VCP inhibitors induce endoplasmic reticulum stress, cause cell cycle arrest, trigger caspase‐mediated cell death and synergistically kill ovarian cancer cells in combination with Salubrinal

Cited by 74 publications

References 60 publications

Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Targeting valosin‐containing protein enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Interleukin‐6 induced overexpression of valosin‐containing protein (VCP)/p97 is associated with androgen‐independent prostate cancer (AIPC) progression

B-Cell Receptor-Associated Protein 31 Regulates the Expression of Valosin-Containing Protein Through Elf2

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