The synthetic tryptanthrin analogue suppresses STAT3 signaling and induces caspase dependent apoptosis via ERK up regulation in human leukemia HL-60 cells.
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.
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Anup S
AS
Pathania
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Suresh
S
Kumar
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India.
Santosh K
SK
Guru
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India.
Shashi
S
Bhushan
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India.
Parduman R
PR
Sharma
Medicinal chemistry division, Indian institute of Integrative Medicine, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
Sravan K
SK
Aithagani
Medicinal chemistry division, Indian institute of Integrative Medicine, Jammu and Kashmir, India.
Parvinder P
PP
Singh
Medicinal chemistry division, Indian institute of Integrative Medicine, Jammu and Kashmir, India.
Ram A
RA
Vishwakarma
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India.
Ajay
A
Kumar
Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu and Kashmir, India; Experimental Breast Cancer Research Laboratory, University of Michigan North Campus Research Complex, Ann Arbor, Michigan, United States of America.
Fayaz
F
Malik
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008856:Microscopy, Fluorescence; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism
D005419:Flavonoids; D011799:Quinazolines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C046243:tryptanthrine; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one