Abstract
Tryptanthrin is a natural product which has been reported to have several medicinal properties. In this study, we tried to investigate the detailed molecular mechanism of its bromo analogue (TBr), a potent cytotoxic agent in the induction of cancer cell death. It was found that TBr primarily targets STAT3 and ERK signaling during the induction of apoptosis in several human leukemia cell lines. In HL-60 cells, TBr treatment caused early down regulation of p-STAT3 with concomitant up regulation of p-ERK which led to the activation of intrinsic and extrinsic pathways of apoptosis. The mechanism of TBr mediated inhibition of p-STAT3 was found to be due to the activation of ubiquitin dependent degradation of tyrosine 705 and serine 727 p-STAT3. As IL-6 is the main driver of the STAT3 pathway, the effect of TBr on cell death was subdued when treated in the combination with IL-6 in HL60 cells. Interestingly, PD98059 significantly reduced the apoptotic effects of TBr, thus showing the direct involvement of p-ERK in TBr mediated cell death. It was further shown that apoptotic protein Bax silencing in HL-60 cells resists TBr mediated ERK dependent apoptosis. In summary, for the first time we report the mechanism of TBr mediated cell death in human leukemia cell lines by targeting STAT3 and ERK pathways.
Highlights
STATs or Signal Transducers and Activators of Transcription control growth, survival and differentiation in cancer cells
Time dependent cell cycle analysis of tryptanthrin bromo (TBr) treated HL-60 cells revealed the appearance of 27% of the cells under subG1 peak in 6 h which was increased to 70% through 24 h (Fig. 1E)
The presence of apoptotic bodies observed in cells stained with hoechst after treatment with TBr further confirmed that TBr triggered cell death by apoptosis (Fig. 1E)
Summary
STATs or Signal Transducers and Activators of Transcription control growth, survival and differentiation in cancer cells. Dysregulation of STATs signaling is frequently observed in leukemia cells that lead to an increase in their proliferation, growth and uncontrolled division [1,2]. STATs are activated by cell surface receptors mainly cytokine receptors via phosphorylation at its tyrosine and serine residues catalyzed by Jak family kinases, intrinsic receptor tyrosine kinases and other cellular tyrosine kinases such as c-Src. Once phosphorylated, STAT proteins form dimers and translocate to the nucleus where it acts as transcription factors for many genes involved in cellular proliferation. AML or Acute myeloid leukemia is a cancer of the myeloid line of blood cells, characterized by the rapid growth and accumulation of white blood cells in the bone marrow, which interferes with the production of normal blood cells. AML is mainly treated by chemotherapy, and natural products play an important role in the treatment of these hematological malignancies [5,6,7]
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