MEK inhibition prevents tumour‐shed transforming growth factor‐β‐induced T‐regulatory cell augmentation in tumour milieu

• DOI: 10.1111/imm.12397
• Publication Date: 2014-10-05T12:15:05Z
• Authors: Dewan M. S. Hossain; Abir K. Panda; Sreeparna Chakrab...; Pushpak Bhattacha...; Kirti Kajal; Suchismita Mohanty; Irene Sarkar; Diptendra K. Sarkar; Santosh K. Kar; Gaurisankar Sa
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Curcumin; Dose-Response Relationship, Drug; Chemistry, Pharmaceutical; Interleukin-2 Receptor alpha Subunit; Breast Neoplasms; Forkhead Transcription Factors; Smad Proteins; MAP Kinase Kinase Kinases; Antineoplastic Agents, Phytogenic; Coculture Techniques; 3. Good health; STAT Transcription Factors; 03 medical and health sciences; Case-Control Studies; Paracrine Communication; Animals; Humans; Nanoparticles; Female; Protein Kinase Inhibitors; Signal Transduction

Tumour progression is associated with immune-suppressive conditions that facilitate the escape of tumour cells from regimen immune cells, subsequently paralysing host defence mechanisms. Induction CD4(+) CD25(+) FoxP3(+) T regulatory (Treg) has been implicated in mechanism, although novel anti-cancer treatment strategies targeting Treg remain unknown. The focus this study to define interaction between and system, i.e. how tolerance starts gradually leads induction adaptive microenvironment. Our identified hyperactivated mitogen-activated protein kinase (MEK)/extracellular signal-regulated (ERK) -signalling as a potential target for reversing cell augmentation breast cancer patients. In more mechanistic detail, pharmacological inhibitors MEK/ERK signalling inhibited transforming growth factor-β (TGF-β) production essentially blocked TGF-β-SMAD3/SMAD4-mediated CD25/interleukin-2 receptor α on T-cell surface. As result high-affinity binding interleukin-2 those was prohibited, causing lack Janus 1 (JAK1)/JAK3-mediated signal transducer activator transcription 3 (STAT3)/STAT5 activation required FoxP3 expression. Finally, radical approach towards safe MEK inhibitor, we validate multi-kinase inhibitor curcumin, especially nano-curcumin made out pure curcumin greater bioavailability; repealing tumour-shed TGF-β-induced augmentation.