Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling

Lee, Chae Ryun; Chun, Jung Nyeo; Kim, Sang Yeob; Park, Soonbum; Kim, Su Hwa; Park, Eun Jung; Kim, In San; Cho, Nam Hyuk; Kim, In Gyu; So, Insuk; Kim, Tae Woo; Jeon, Ju Hong

doi:10.1016/j.bcp.2012.05.009

Cited by 31 publications

(20 citation statements)

References 38 publications

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“…6E). In addition, treatment with cyclosporin A (CsA), a Ca 2þ signaling inhibitor (37), also blocked the effect of T-MPs on CD80 and CD86 upregulation (Fig. 6F).…”

Section: Ros-triggered Lysosomal Calcium Signaling Upregulates Cd80/ mentioning

confidence: 89%

Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

Wei

Zhang

et al. 2018

Cancer Immunology Research

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Tumor cell-derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP-driven lysosomal centripetal migration, promotes the formation of MHC class I-tumor antigen peptide complexes. Concurrently, endocytosis of T-MPs results in the upregulation of CD80 and CD86. T-MP-increased ROS activate lysosomal Ca channel Mcoln2, leading to Ca release. Released Ca activates transcription factor EB (TFEB), a lysosomal master regulator that directly binds to CD80 and CD86 promoters, promoting gene expression. These findings elucidate a pathway through which DCs efficiently present tumor antigen from T-MPs to CD8 T cells, potentiating T-MPs as a novel tumor cell-free vaccine with clinical applications. .

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“…6E). In addition, treatment with cyclosporin A (CsA), a Ca 2þ signaling inhibitor (37), also blocked the effect of T-MPs on CD80 and CD86 upregulation (Fig. 6F).…”

Section: Ros-triggered Lysosomal Calcium Signaling Upregulates Cd80/ mentioning

confidence: 89%

Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

Wei

Zhang

et al. 2018

Cancer Immunology Research

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“…Although beyond the scope of present study, it would be interesting to see if the pathway activated by the MIF/CD74 couple (AMPK vs PI3K pathways) depends on differentiation of the cancer cells. Recent studies indicate that MIF/CD74 activation of AMPK pathway inhibits TGF- β -induced EMT (Cufi et al , 2010; Heinrichs et al , 2011; Lee et al , 2013), and suppresses cell proliferation and migration in tumour cells (Kim et al , 2012; Lee et al , 2012a). In other words, activation of this pathway may represent an attempt to prevent EMT.…”

Section: Discussionmentioning

confidence: 99%

CD74: a new prognostic factor for patients with malignant pleural mesothelioma

et al. 2014

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Background:The pro-inflammatory cytokine migration inhibitory factor (MIF) and its receptor CD74 have been proposed as possible therapeutic targets in several cancers. We studied the expression of MIF and CD74 together with calretinin in specimens of malignant pleural mesothelioma (MPM), correlating their expression levels with clinico-pathologic parameters, in particular overall survival (OS).Methods:Migration inhibitory factor, CD74, and calretinin immunoreactivity were investigated in a tissue microarray of 352 patients diagnosed with MPM. Protein expression intensities were semiquantitatively scored in the tumour cells and in the peritumoral stroma. Markers were matched with OS, age, gender, and histological subtype.Results:Clinical data from 135 patients were available. Tumour cell expressions of MIF and CD74 were observed in 95% and 98% of MPM specimens, respectively, with a homogenous distribution between the different histotypes. CD74 (P<0.001) but not MIF overexpression (P=0.231) emerged as an independent prognostic factor for prolonged OS. High expression of tumour cell calretinin correlated with the epithelioid histotype and was also predictive of longer OS (P<0.001). When compared with previously characterised putative epithelial-to-mesenchymal transition markers, CD74 correlated positively with tumoral PTEN and podoplanin expressions, but was inversely related with periostin expression.Conclusions:High expression of CD74 is an independent prognostic factor for prolonged OS in mesothelioma patients.

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“…Lee et al. [91] demonstrated that CsA might have a survival benefit in metastatic PCa that relapses and progresses to CRPC. It has also been shown that a combination of CsA with EGFR or AKT inhibitors may have clinical application due to its efficiency in inhibiting cancer growth.…”

Section: Abc Transportersmentioning

confidence: 99%

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

Leão¹,

Domingos

Figueiredo

et al. 2017

Urol Int

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the second most common cause of cancer-related mortality among men in the developed world. Conventional anti-PCa therapies include surgery, radiation, hormonal ablation, and chemotherapy. Despite increasing efforts, these therapies are not effective for patients with advanced and/or metastatic disease. In most cases, cancer therapies fail due to an incomplete depletion of tumor cells, resulting in tumor relapse. The cancer stem cell (CSC) hypothesis is an emerging model that explains many of the molecular characteristics of oncological disease as well as the tendency of cancers to relapse, metastasize, and develop resistance to conventional therapies. CSCs are a reservoir of cancer cells that exhibit properties of self-renewal and the ability to reestablish the heterogeneous tumor cell population. The existence of PCa stem cells offers a theoretical explanation for many uncertainties regarding PCa and also for treatment resistance and disease progression once clinical cure is achieved. Therapies targeting CSCs might therefore lead to more effective cancer treatments, divergent from a traditional anti-proliferative approach, based on tumor bulk reduction accompanied by CSC-specific inhibition. Here, we focus on reviewing the historical perspective as well as concepts regarding stem cells and CSCs in PCa. In addition, we will report possible strategies and new clinical approaches that address the CSC-based concept of tumorigenesis in PCa.

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Cyclosporin A suppresses prostate cancer cell growth through CaMKKβ/AMPK-mediated inhibition of mTORC1 signaling

Cited by 31 publications

References 38 publications

Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

Mechanisms by Which Dendritic Cells Present Tumor Microparticle Antigens to CD8+ T Cells

CD74: a new prognostic factor for patients with malignant pleural mesothelioma

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

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