Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late-stage breast cancer

Hitomi Motomura; Ayaka Ozaki; Shoma Tamori; Chotaro Onaga; Yuka Nozaki; Yuko Waki; Ryoko Takasawa; Kazumi Yoshizawa; Yasunari Mano; Tsugumichi Sato; Kazunori Sasaki; Hitoshi Ishiguro; Yohei Miyagi; Yoji Nagashima; Kouji Yamamoto; Keiko Sato; Takehisa Hanawa; Sei-Ichi Tanuma; Shigeo Ohno; Kazunori Akimoto

doi:10.3892/ol.2021.12808

Glyoxalase 1 and protein kinase Cλ as potential therapeutic targets for late-stage breast cancer

Oncol Lett. 2021 Jul;22(1):547. doi: 10.3892/ol.2021.12808. Epub 2021 May 24.

Authors

Hitomi Motomura¹, Ayaka Ozaki¹, Shoma Tamori¹, Chotaro Onaga¹, Yuka Nozaki¹, Yuko Waki¹, Ryoko Takasawa², Kazumi Yoshizawa², Yasunari Mano², Tsugumichi Sato², Kazunori Sasaki³, Hitoshi Ishiguro^{4

5}, Yohei Miyagi⁶, Yoji Nagashima⁷, Kouji Yamamoto⁸, Keiko Sato⁹, Takehisa Hanawa², Sei-Ichi Tanuma^{1

10}, Shigeo Ohno^{3

11}, Kazunori Akimoto¹

Affiliations

¹ Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
² Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
³ Department of Molecular Biology, Yokohama City University, School of Medicine, Kanagawa 236-0004, Japan.
⁴ Department of Urology, Yokohama City University Graduate School of Medicine, Kanagawa 236-0004, Japan.
⁵ Photocatalyst Group, Research and Development Department, Kanagawa Institute of Industrial Science and Technology, Kanagawa 210-0821, Japan.
⁶ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa 241-8515, Japan.
⁷ Department of Surgical Pathology, Tokyo Women's Medical University Hospital, Tokyo 162-8666, Japan.
⁸ Department of Biostatistics, Yokohama City University, School of Medicine, Kanagawa 236-0004, Japan.
⁹ Department of Information Sciences, Faculty of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan.
¹⁰ Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Chiba 278-8510, Japan.
¹¹ Department of Cancer Biology, Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo 113-8421, Japan.

Abstract

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III-IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08-5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.

Keywords: breast cancer; glyoxalase 1; immunohistochemistry; protein kinase Cλ.

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research (C) of JSPS (grant no. 20K07207), a Grant-in-Aid for JSPS Research Fellows (grant no. 20J11980), JSPS KAKENHI Grant Number JP 16H06277 (CoBiA), the MEXT's Promotion Plan for the Platform of Human Resource Development for Cancer project, 2012-2017, Translational Research Center, Research Institute for Science and Technology, Tokyo University of Science (S1411013) and Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan.