title: MEK inhibition prevents tumour-shed transforming growth factor-β-induced T-regulatory cell augmentation in tumour milieu.
abstract: Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from the regimen of immune cells, subsequently paralysing the host defence mechanisms. Induction of CD4(+)  CD25(+)  FoxP3(+) T regulatory (Treg) cells has been implicated in the tumour immune escape mechanism, although the novel anti-cancer treatment strategies targeting Treg cells remain unknown. The focus of this study is to define the interaction between tumour and immune system, i.e. how immune tolerance starts and gradually leads to the induction of adaptive Treg cells in the tumour microenvironment. Our study identified hyperactivated mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) -signalling as a potential target for reversing Treg cell augmentation in breast cancer patients. In more mechanistic detail, pharmacological inhibitors of MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production in tumour cells that essentially blocked TGF-β-SMAD3/SMAD4-mediated induction of CD25/interleukin-2 receptor α on CD4(+) T-cell surface. As a result high-affinity binding of interleukin-2 on those cells was prohibited, causing lack of Janus kinase 1 (JAK1)/JAK3-mediated signal transducer and activator of transcription 3 (STAT3)/STAT5 activation required for FoxP3 expression. Finally, for a more radical approach towards a safe MEK inhibitor, we validate the potential of multi-kinase inhibitor curcumin, especially the nano-curcumin made out of pure curcumin with greater bioavailability; in repealing tumour-shed TGF-β-induced Treg cell augmentation.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, India.
authors.forename: Dewan M S
authors.initials: DM
authors.lastname: Hossain
authors.forename: Abir K
authors.initials: AK
authors.lastname: Panda
authors.forename: Sreeparna
authors.initials: S
authors.lastname: Chakrabarty
authors.forename: Pushpak
authors.initials: P
authors.lastname: Bhattacharjee
authors.forename: Kirti
authors.initials: K
authors.lastname: Kajal
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.forename: Irene
authors.initials: I
authors.lastname: Sarkar
authors.forename: Diptendra K
authors.initials: DK
authors.lastname: Sarkar
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Kar
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002626:Chemistry, Pharmaceutical; D018920:Coculture Techniques; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D019899:Paracrine Communication / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D020930:MAP Kinase Kinase Kinases; D003474:Curcumin
keywords: breast cancer; janus kinase/signal transducer and activator of transcription; mitogen-activated protein kinase kinase/extracellular signal-regulated kinase; nano-curcumin; regulatory T cells; transforming growth factor-β