Role of RACK1 on cell proliferation, adhesion, and bortezomib-induced apoptosis in multiple myeloma

Zhang, Linlin; Xu, Ya Long; Wang, Li; Hong, Liu

doi:10.1016/j.ijbiomac.2018.10.034

Cited by 13 publications

(10 citation statements)

References 24 publications

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“…Application of these inhibitor compounds will not only be useful as HTAs, but many other diseases where RACK1 expression has been implicated in disease progression. For example, in cancer metastasis [50–52], acute pancreatitis [53], Cardiovascular disease [54], plant pathogenic viruses using IRES [16], and Leishmaniasis [55], RACK1 expression has been shown to produce poor prognosis. Therefore, chemical inhibitor molecule of RACK1 protein should be effective in alleviating the disease progression in these circumstances as well.…”

Section: Discussionmentioning

confidence: 99%

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

et al. 2019

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Due to the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs. Viruses require host factors to translate their transcripts, and targeting the host factor(s) offers a unique opportunity to develop broad antiviral drugs. It is well documented that some viruses utilize a host protein, Receptor for Activated C Kinase 1 (RACK1), to translate their mRNAs using a viral mRNA secondary structure known as the Internal Ribosomal Entry Site (IRES). RACK1 is essential for the translation of many viruses including hepatitis C (HCV), polio, Drosophila C (DCV), Dengue, Cricket Paralysis (CrpV), and vaccinia viruses. In addition, HIV-1 and Herpes Simplex virus (HSV-1) are known to use IRES as well. Therefore, host RACK1 protein is an attractive target for developing broad antiviral drugs. Depletion of the host’s RACK1 will potentially inhibit virus replication. This background study has led us to the development of novel antiviral therapeutics, such as RACK1 inhibitors. By utilizing the crystal structure of the RACK1A protein from the model plant Arabidopsis and using a structure based drug design method, dozens of small compounds were identified that could potentially bind to the experimentally determined functional site of the RACK1A protein. The SPR assays showed that the small compounds bound strongly to recombinant RACK1A protein. Here we provide evidence that the drugs show high efficacy in inhibition of HSV-1 proliferation in a HEp-2 cell line. The drug showed similar efficacy as the available anti-herpes drug acyclovir and showed supralinear effect when applied in a combinatorial manner. As an increasing number of viruses are reported to use host RACK1 proteins, and more than 100 diverse animals and plant disease-causing viruses are known to use IRES-based translation, these drugs can be established as host-targeted broad antiviral drugs.

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Section: Discussionmentioning

confidence: 99%

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

et al. 2019

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“…The general abnormal vs. normal cell comparison was not powered to identify this upregulation, since the translocation only occurred in a single patient in our cohort. Additionally, we discovered upregulation of GNB2L1 (also known as RACK1; up in SMM-2, SMM-3, MM-6), a known oncogene in other cancers 35,36 that has recently been reported to be upregulated in myeloma cell lines 35,36 , but not yet in clinical samples. Among upregulated genes, we also found the histone gene HIST1H1C (MGUS-3, SMM-2, SMM-3, SMM-8, MM-6), the cell surface markers CD48 (MGUS-3, SMM-8) and CD59 (MGUS-3, SMM-2, SMM-3, SMM-8, SMM-Fig.…”

Section: Within-patient Abnormal Vs Normal Cell Comparisons Highlight...mentioning

confidence: 93%

Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis

et al. 2022

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Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.

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“…The general neoplastic vs. normal cell comparison was not powered to identify this upregulation, since the translocation only occurred in a single patient in our cohort. Additionally, we discovered upregulation of GNB2L1 (also known as RACK1; up in SMM-2, SMM-3, MM-6), a known oncogene in other cancers 26,27 that has recently been reported to be upregulated in myeloma cell lines, 26,27 but not yet in clinical samples. Among upregulated genes, we also found the histone gene HIST1H1C (MGUS-3, SMM-2, SMM-3, SMM-8, MM-6), the cell surface markers CD48 (MGUS-3, SMM-8) and CD59 (MGUS-3, SMM-2, SMM-3, SMM-8, SMM-10), and the proto-oncogene MYC (MGUS-3, SMM-2, MM-6) (Fig.…”

Section: Within-patient Neoplastic Vs Normal Cell Comparisons Highlig...mentioning

confidence: 94%

Single Cell Characterization of Myeloma and its Precursor Conditions Reveals Transcriptional Signatures of Early Tumorigenesis

Boiarsky

Haradhvala

Alberge

et al. 2022

Preprint

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Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generated and analyzed single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enabled discovery of novel, patient-specific transcriptional changes. Using Bayesian Non-Negative Matrix Factorization, we discovered 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identified a signature that is uniformly lost in neoplastic cells across disease stages. Finally, we demonstrated that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, paving the way for exploration of personalized treatment approaches prior to malignant disease.

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Role of RACK1 on cell proliferation, adhesion, and bortezomib-induced apoptosis in multiple myeloma

Cited by 13 publications

References 24 publications

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis

Single Cell Characterization of Myeloma and its Precursor Conditions Reveals Transcriptional Signatures of Early Tumorigenesis

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