| 11. |
- Lindell, Emma, et al.
(författare)
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Exploring the Enigma : The Role of the Epithelial Protein Lost in Neoplasm in Normal Physiology and Cancer Pathogenesis
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:9
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Forskningsöversikt (refereegranskat)abstract
- The cytoskeleton plays a pivotal role in maintaining the epithelial phenotype and is vital to several hallmark processes of cancer. Over the past decades, researchers have identified the epithelial protein lost in neoplasm (EPLIN, also known as LIMA1) as a key regulator of cytoskeletal dynamics, cytoskeletal organization, motility, as well as cell growth and metabolism. Dysregulation of EPLIN is implicated in various aspects of cancer progression, such as tumor growth, invasion, metastasis, and therapeutic resistance. Its altered expression levels or activity can disrupt cytoskeletal dynamics, leading to aberrant cell motility and invasiveness characteristic of malignant cells. Moreover, the involvement of EPLIN in cell growth and metabolism underscores its significance in orchestrating key processes essential for cancer cell survival and proliferation. This review provides a comprehensive exploration of the intricate roles of EPLIN across diverse cellular processes in both normal physiology and cancer pathogenesis. Additionally, this review discusses the possibility of EPLIN as a potential target for anticancer therapy in future studies.
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| 12. |
- Lindell, Emma, et al.
(författare)
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Quiescent Cancer Cells : A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:4
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Forskningsöversikt (refereegranskat)abstract
- Quiescent cancer cells (QCCs) are nonproliferating cells arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, and some treatments could further lead to a higher proportion of QCCs in tumors. QCCs are also associated with cancer recurrence since they can re-enter a proliferative state when conditions are favorable. As QCCs lead to drug resistance and tumor recurrence, there is a great need to understand the characteristics of QCCs, decipher the mechanisms that regulate the proliferative–quiescent transition in cancer cells, and develop new strategies to eliminate QCCs residing in solid tumors. In this review, we discussed the mechanisms of QCC-induced drug resistance and tumor recurrence. We also discussed therapeutic strategies to overcome resistance and relapse by targeting QCCs, including (i) identifying reactive quiescent cancer cells and removing them via cell-cycle-dependent anticancer reagents; (ii) modulating the quiescence-to-proliferation switch; and (iii) eliminating QCCs by targeting their unique features. It is believed that the simultaneous co-targeting of proliferating and quiescent cancer cells may ultimately lead to the development of more effective therapeutic strategies for the treatment of solid tumors.
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| 13. |
- Lu, Xi, et al.
(författare)
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Identification of ATF3 as a novel protective signature of quiescent colorectal tumor cells
- 2023
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 14:10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is the third most common cancer and the second leading cause of death in the world. In most cases, drug resistance and tumor recurrence are ultimately inevitable. One obstacle is the presence of chemotherapy-insensitive quiescent cancer cells (QCCs). Identification of unique features of QCCs may facilitate the development of new targeted therapeutic strategies to eliminate tumor cells and thereby delay tumor recurrence. Here, using single-cell RNA sequencing, we classified proliferating and quiescent cancer cell populations in the human colorectal cancer spheroid model and identified ATF3 as a novel signature of QCCs that could support cells living in a metabolically restricted microenvironment. RNA velocity further showed a shift from the QCC group to the PCC group indicating the regenerative capacity of the QCCs. Our further results of epigenetic analysis, STING analysis, and evaluation of TCGA COAD datasets build a conclusion that ATF3 can interact with DDIT4 and TRIB3 at the transcriptional level. In addition, decreasing the expression level of ATF3 could enhance the efficacy of 5-FU on CRC MCTS models. In conclusion, ATF3 was identified as a novel marker of QCCs, and combining conventional drugs targeting PCCs with an option to target QCCs by reducing ATF3 expression levels may be a promising strategy for more efficient removal of tumor cells.
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| 14. |
- Ma, Ran, et al.
(författare)
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Estrogen Receptor β as a Therapeutic Target in Breast Cancer Stem Cells.
- 2017
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 109:3, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer.Methods: We characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ERβ-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n = 4 or 5 per group) were used to study the role of ERs during tumorigenesis.Results: We identified an absence of ERα but upregulation of ERβ in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ERβ caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ERβ-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ERβ (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts.Conclusion: We identify ERβ as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.
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| 15. |
- Mao, Yumeng, et al.
(författare)
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IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
- 2016
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Ingår i: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 128:11, s. 1475-1489
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
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| 16. |
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| 17. |
- Pellegrini, Paola, 1986-, et al.
(författare)
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Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:13
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Tidskriftsartikel (refereegranskat)abstract
- 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 2 alpha (eIF2 alpha), 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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| 18. |
- Peng, Xuerun, et al.
(författare)
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Emetine, a small molecule natural product, displays potent anti-gastric cancer activity via regulation of multiple signaling pathways
- 2023
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer. - 0344-5704 .- 1432-0843. ; 91:4, s. 303-315
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Tidskriftsartikel (refereegranskat)abstract
- Background Gastric cancer (GC) is a life-threatening malignant tumor with high incidence rate. Despite great progress, there are still many GC sufferers that cannot benefit from the existing anti-GC treatments. Therefore, it is still necessary to develop novel medicines against GC. Emetine, a natural small molecule isolated from Psychotria ipecacuanha, has been broadly used for medicinal purposes including cancer treatment. Here, we conducted a comprehensive study on the anti-GC effects of emetine and the related mechanisms of action.Methods The cell viability was evaluated by MTT and colony formation assay. Cellular proliferation and apoptosis were analyzed by edu incorporation assay and Annexin V-PI staining, respectively. Moreover, wound healing assay and transwell invasion assay were conducted to detect cell migration and invasion after treatment with emetine. To elucidate the molecular mechanism involved in the anti-GC effects of emetine, RNA sequencing and functional enrichment analysis were carried out on MGC803 cells. Then, the western blot analysis was performed to further verify the anti-GC mechanism of emetine. In vivo anti-tumor efficacy of emetine was evaluated in the MGC803 xenograft model.Results MTT and colony formation assay exhibited a strong potency of emetine against GC cell growth, with IC50 values of 0.0497 μM and 0.0244 μM on MGC803 and HGC-27 cells, respectively. Further pharmacodynamic studies revealed that emetine restrained the growth of GC cells mainly via proliferation inhibition and apoptosis induction. Meanwhile, emetine also had the ability to block GC cell migration and invasion. The results of RNA sequencing and western blot showed that emetine acted through regulating multiple signaling pathways, including not only MAPKs and Wnt/β-catenin signaling axes, but also PI3K/AKT and Hippo/YAP signaling cascades that were not found in other tumor types. Notably, the antitumor efficacy of emetine could also be observed in MGC803 xenograft models.Conclusion Our data demonstrate that emetine is a promising lead compound and even a potential drug candidate for GC treatment, deserving further structural optimization and development.
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| 19. |
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