MK615 Suppresses Hypoxia Tolerance by Up-regulation of E-cadherin in Colorectal Cancer Cells With Mutant KRAS

Kensuke Nishi; Toshiyuki Tsunoda; Yoshinori Uchida; Takayuki Sueta; Motohiro Sawatsubashi; Takafumi Yamano; Yasuko Hashiguchi; Anthony Swain; Senji Shirasawa; Toshifumi Sakata

doi:10.21873/anticanres.14468

MK615 Suppresses Hypoxia Tolerance by Up-regulation of E-cadherin in Colorectal Cancer Cells With Mutant KRAS

Anticancer Res. 2020 Aug;40(8):4687-4694. doi: 10.21873/anticanres.14468.

Authors

Kensuke Nishi^{1

2

3}, Toshiyuki Tsunoda^{2

4}, Yoshinori Uchida¹, Takayuki Sueta¹, Motohiro Sawatsubashi⁵, Takafumi Yamano³, Yasuko Hashiguchi⁴, Anthony Swain², Senji Shirasawa^{2

4}, Toshifumi Sakata⁶

Affiliations

¹ Department of Otorhinolaryngology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
² Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
³ Section of Otolaryngology, Department of Medicine, Fukuoka Dental College, Fukuoka, Japan.
⁴ Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.
⁵ Department of Otolaryngology, Fukuoka University Chikushi Hospital, Fukuoka, Japan.
⁶ Department of Otorhinolaryngology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan sakata@fukuoka-u.ac.jp.

PMID: 32727793
DOI: 10.21873/anticanres.14468

Abstract

Background/aim: The Japanese apricot "Prunus mume" is a traditional Japanese medicine. MK615, a compound extract from Prunus mume has been reported to have anti-tumor effects. Herein, we used 3D floating (3DF) culture to evaluate the anticancer effects of MK615 against human colorectal cancer (CRC) cells that contain mutant (mt) KRAS.

Materials and methods: HKe3 cells exogenously expressing mtKRAS (HKe3-mtKRAS) were treated with MK615 in 3DF cultures. The protein levels of hypoxia-inducible factor 1 (HIF-1) and E-cadherin were quantified by western blotting.

Results: MtKRAS enhanced hypoxia tolerance via up-regulation of HIF-1. The expression of HIF-1 protein was suppressed by constitutive overexpression of E-cadherin in CRC HCT116 spheroids. MK615 increased the expression of E-cadherin and decreased the expression of HIF-1 in HKe3-mtKRAS. These results suggest that MK615 suppresses hypoxia tolerance by up-regulation of E-cadherin in CRC cells with mtKRAS.

Conclusion: MK615 exhibits properties useful for the potential treatment of CRC patients with mtKRAS.

Keywords: E-cadherin; HIF; KRAS; MK615; Prunus mume; colon cancer.

MeSH terms

Antigens, CD / metabolism*
Cadherins / metabolism*
Cell Hypoxia / drug effects
Cell Hypoxia / physiology*
Cell Line, Tumor
Cell Proliferation / drug effects
Colonic Neoplasms / metabolism*
Colorectal Neoplasms / drug therapy
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
HCT116 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Plant Extracts / pharmacology*
Proto-Oncogene Proteins p21(ras) / metabolism*
Prunus / chemistry
Transcriptional Activation / drug effects
Up-Regulation / drug effects*

Substances

Antigens, CD
CDH1 protein, human
Cadherins
Hypoxia-Inducible Factor 1, alpha Subunit
KRAS protein, human
Plant Extracts
Proto-Oncogene Proteins p21(ras)