JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.
2016; 2: 16028
A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets.
View details for DOI 10.1038/celldisc.2016.28
View details for PubMedID 27648299
View details for PubMedCentralID PMC5012007
An old herbal medicine with a potentially new therapeutic application in inflammatory bowel disease
INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE
2011; 4 (4): 309–19
Inflammatory Bowel Disease (IBD) is a chronic and frequently disabling inflammatory disorder of the intestine. New developments in IBD therapy are primarily focused on biologic treatments; however, they are both expensive and associated with significant side effects. Here, we provide the first preclinical evidence that YunNan BaiYao (YNBY), a well-known traditional Chinese herbal remedy frequently used for treating hemorrhages and wounds, can effectively alleviate experimental colitis. Oral administration of YNBY in drinking water significantly reduced the disease activities of both DSS- and TNBS-induced experimental colitis. Mechanistic studies revealed that the effectiveness of YNBY was not due to an anti-bacterial function since YNBY had no effect on E. coli growth. Rather, it exhibited an anti-inflammatory or immunosuppressive function: In the DSS colitis model, YNBY treatment decreased the levels of several pro-inflammatory cytokines in colonic mucosa, including TNFα, IL-12p40, and IL-17. Similar cytokine changes were also observed in mouse serum, suggesting that systemic changes in general reflect the changes in the affected colon. Significant down-regulation of IL-12p40 and IL-17, in addition to IFNγ, was also seen in TNBS-colitis model. Another potential mechanism for the anti-inflammatory effects of YNBY involves the selective suppression of pro-inflammatory immune cells: YNBY effectively suppressed the growth of multiple T- and B-lymphocytes, including Molt-4, Jurkat, and EBV-transformed human B-lymphocytes, more potently than 6-mecaptopurine (6-MP) and 5-aminosalicylic acid (5-ASA), two of the most commonly used first-line drugs in IBD therapy. In sharp contrast, YNBY exhibited no cytotoxicity to colonic epithelial cells (Caco-2 cells), even at the concentration 10-fold higher than that used in the lymphocyte model; and instead promoted cell spreading and wound healing. These results strongly suggest that YNBY not only has effective anti-inflammatory properties through suppressing lymphocyte growth and pro-inflammatory cytokine expression, but also can promote intestinal epithelial wound-healing and repair. Therefore, YNBY demonstrates strong potential as an alternative herbal therapy for IBD.
View details for Web of Science ID 000208701500008
View details for PubMedID 22140602
View details for PubMedCentralID PMC3228586