The multi-targeted kinase inhibitor sunitinib induces apoptosis in colon cancer cells via PUMA.
Constitutive activation of pro-survival kinases has become a promising target of small molecules with an increasing interest in developing multi-targeted agents. The mechanisms underlying the responsiveness to most agents targeting cancer specific survival pathways are still poorly understood but critical for their clinical application. In this study, we found that sunitinib, a small molecule inhibitor of multiple tyrosine kinases including VEGFRs and PDGFRs induces apoptosis and inhibits cell growth in colon cancer cells in cell culture and xenograft models via the BH3-only protein PUMA. Sunitinib treatment induced PUMA transcription via the AKT/FoxO3a axis. PUMA, BH3 mimetics, or 5-Flurourical sensitized colon cancer cells to sunitinib-induced apoptosis. Furthermore, PUMA was induced by sunitinib treatment in xenograft tumors, and deficiency in PUMA significantly suppressed the anti-tumor effects of sunitinib. Our study suggests that PUMA-mediated apoptosis is important for the therapeutic responses to sunitinib, and activation of the mitochondrial pathway by BH3 mimetics or PUMA manipulation may be useful for improving the antitumor activity of sunitinib. Modulation of PUMA and selective Bcl-2 family members might be potential biomarkers for predicting sunitinib responses.
Departments of Pathology, and Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Jing
J
Sun
Quanhong
Q
Sun
Matthew F
MF
Brown
Crissy
C
Dudgeon
Julie
J
Chandler
Xiang
X
Xu
Yongqian
Y
Shu
Lin
L
Zhang
Jian
J
Yu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006652:Histological Techniques; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology*; D008156:Luciferases; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077210:Sunitinib
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D017931:DNA Primers; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007211:Indoles; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D008156:Luciferases; D051058:Oncogene Protein v-akt; D000077210:Sunitinib