Superoxide activates mTOR-eIF4E-Bax route to induce enhanced apoptosis in leukemic cells.
Mammalian target of rapamycin (mTOR) is a central kinase that regulates cell survival, proliferation and translation. Reactive oxygen species (ROS) are second messengers with potential in manipulating cellular signaling. Here we report that two ROS generating phytochemicals, hydroxychavicol and curcumin synergize in leukemic cells in inducing enhanced apoptosis by independently activating both mitogen activated protein kinase (MAPK) (JNK and P(38)) and mTOR pathways. Low level transient ROS generated after co-treatment with these phytochemicals led to activation of these two pathways. Both mTOR and MAPK pathways played important roles in co-treatment-induced apoptosis, by knocking down either mTOR or MAPKs inhibited apoptosis. Activation of mTOR, as evident from phosphorylation of its downstream effector eukaryotic translation initiation factor 4E-binding protein 1, led to release of eukaryotic translation initiation factor 4E (eIF4E) which was subsequently phosphorylated by JNK leading to translation of pro-apoptotic proteins Bax and Bad without affecting the expression of anti-apoptotic protein Bcl-xl. Our data suggest that mTOR and MAPK pathways converge at eIF4E in co-treatment-induced enhanced apoptosis and provide mechanistic insight for the role of mTOR activation in apoptosis.
Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology (IICB), 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India.
Jaydeep
J
Chaudhuri
Avik Acharya
AA
Chowdhury
Nabendu
N
Biswas
Anirban
A
Manna
Saurav
S
Chatterjee
Tulika
T
Mukherjee
Utpal
U
Chaudhuri
Parasuraman
P
Jaisankar
Santu
S
Bandyopadhyay
D017209:Apoptosis; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; D051028:bcl-2-Associated X Protein; D013481:Superoxides; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases