Apremilast induces apoptosis of human colorectal cancer cells with mutant KRAS

Nishi, K., Luo, H., Ishikura, S., Doi, K., Iwaihara, Y., Wills, L., Baillie, G. S. , Sakata, T., Shirasawa, S. and Tsunoda, T. (2017) Apremilast induces apoptosis of human colorectal cancer cells with mutant KRAS. Anticancer Research, 37(7), pp. 3833-3839. (doi: 10.21873/anticanres.11762) (PMID:28668883)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Baillie, Professor George and WILLS, LAUREN
• Authors: Nishi, K., Luo, H., Ishikura, S., Doi, K., Iwaihara, Y., Wills, L., Baillie, G. S., Sakata, T., Shirasawa, S., and Tsunoda, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Anticancer Research
• Publisher: International Institute of Anticancer Research
• ISSN: 0250-7005
• ISSN (Online): 1791-7530
• Copyright Holders: Copyright © 2017 International Institute of Anticancer Research
• First Published: First published in Anticancer Research 37(7):3833-3839
• Publisher Policy: Reproduced with the permission of the publisher