RT Journal Article
SR Electronic
T1 Apremilast Induces Apoptosis of Human Colorectal Cancer Cells with Mutant <em>KRAS</em>
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 3833
OP 3839
VO 37
IS 7
A1 KENSUKE NISHI
A1 HAO LUO
A1 SHUHEI ISHIKURA
A1 KEIKO DOI
A1 YURI IWAIHARA
A1 LAUREN WILLS
A1 GEORGE S. BAILLIE
A1 TOSHIFUMI SAKATA
A1 SENJI SHIRASAWA
A1 TOSHIYUKI TSUNODA
YR 2017
UL http://ar.iiarjournals.org/content/37/7/3833.abstract
AB Background/Aim: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS). Materials and Methods: Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy or western blot in HKe3-wtPDE4B2, HKe3-mtPDE4B2, HKe3-wtKRAS and mtKRAS cells treated with or without apremilast in 3DC. Tumourigenicity was assessed in nude mice assay using these cells. Results: Apremilast did not inhibit the proliferation of HKe3-wtPDE4B2 cells or HKe3-mtKRAS in two-dimensional cultures, whereas the number of apoptotic HKe3-wtPDE4B2 cells and HKe3-mtKRAS cells increased after apremilast treatment in 3DC, leading to formation of a luminal cavity. Tumour growth in nude mice was dramatically reduced by intraperitoneal injection of apremilast. Notably, a decreased level of caspase-1 expression was observed in HKe3-wtPDE4B2 and HKe3-mtKRAS cells. Conclusion: Apremilast induces tumour regression in nude mice, possibly by inducing caspase-1 expression.