Smac mimetic with TNF-α targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields.
Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-α (TNF-α) was able to inhibit the production of ROS, inhibit glycolysis through Pim-1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-α or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-α is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields.
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, U.S.A.
Goodwin G
GG
Jinesh
AstraZeneca, Boston, MA 02451, U.S.A.
Naomi M
NM
Laing
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, U.S.A. akamat@mdanderson.org.
Ashish M
AM
Kamat
D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000008:administration & dosage / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014170:Transformation, Genetic / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
BAD; FasL; Pim-1 isoforms; Smac mimetic; blebbishields; reactive oxygen species