Targeting Translation of mRNA as a Therapeutic Strategy in Cancer

Pal, Ipsita; Safari, Maryam; Jovanović, Marko; Bates, Susan E.; Deng, Chao

doi:10.1007/s11899-019-00530-y

Cited by 35 publications

(36 citation statements)

References 99 publications

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“…Protein synthesis inhibition is a validated target for anticancer drugs [50]. Omacetaxine mepesuccinate is a semisynthetic analog of homoharringtonine that has been approved for treatment of chronic myeloid leukemia (CML) [51].…”

Section: Discussionmentioning

confidence: 99%

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

Pellegrini

Selvaraju

Faustini

et al. 2020

IJMS

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The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib.

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Section: Discussionmentioning

confidence: 99%

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

Pellegrini

Selvaraju

Faustini

et al. 2020

IJMS

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“…Osteosarcoma, as a common malignant bone cancer, is prevailing in childhood and adolescence (1). It has a characteristic of immortal cell proliferation as well as high levels of mRNA translation (2). The main treatment approaches are composed of neoadjuvant chemotherapy, surgery as well as adjuvant chemotherapy (3).…”

Section: Introductionmentioning

confidence: 99%

C3AR1 mRNA as a Potential Therapeutic Target Associates With Clinical Outcomes and Tumor Microenvironment in Osteosarcoma

Zou

Liu²,

Wang³

et al. 2021

Front. Med.

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Objective: Targeting cancer-specific messenger RNAs (mRNAs) may offer novel insights into therapeutic strategies in osteosarcoma. This study aimed to discover possible osteosarcoma-specific mRNA and probe its biological functions.Methods: Based on mRNA-seq data from the TARGET database, stromal and immune scores were estimated for each osteosarcoma sample via the ESTIMATE algorithm. Stromal and immune mRNAs were obtained via integration of differentially expressed mRNAs between high and low stromal / immune score groups. Among hub and prognostic mRNAs, C3AR1 mRNA was focused and its prognostic value was assessed. The associations between C3AR1 mRNA and immune cells were analyzed via the CIBERSORT algorithm. Its expression was verified in osteosarcoma tissues and cells by RT-qPCR and western blot. The functions of C3AR1 were investigated by a series of experiments.Results: Low stromal and immune scores were both indicative of unfavorable outcomes for osteosarcoma patients. Eighty-eight up-regulated and seven down-regulated stromal and immune mRNAs were identified. Among 30 hub mRNAs, low expression of C3AR1 mRNA indicated worse outcomes than its high expression. There was a lower mRNA expression of C3AR1 in metastatic than non-metastatic osteosarcoma. C3AR1 mRNA was closely correlated to various immune cells such as macrophages. C3AR1 was verified to be down-regulated in osteosarcoma tissues and cells. Its overexpression suppressed proliferation, migration and invasion and induced apoptosis in osteosarcoma cells.Conclusion: C3AR1 mRNA could be a promising therapeutic target for osteosarcoma, linked with prognosis and tumor microenvironment.

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“…The synergy between OTS167 and TKIs in combination treatment experiments in vitro and in vivo suggests that OTS167 may induce cell death in a manner other than through cooperative FLT3 kinase inhibition. Drugs targeting translation initiation factors eIF4A, eIF4E, 4E-BP1, as well as translation elongation have been developed and show encouraging results in several cancer models and clinical trials 49 . OTS167 treatment resulted in the downregulation of mutant FLT3 expression due to inhibition of FLT3 translation.…”

Section: Discussionmentioning

confidence: 99%

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

et al. 2021

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Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E–binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.

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Targeting Translation of mRNA as a Therapeutic Strategy in Cancer

Cited by 35 publications

References 99 publications

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

C3AR1 mRNA as a Potential Therapeutic Target Associates With Clinical Outcomes and Tumor Microenvironment in Osteosarcoma

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

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