GLO 1 and PKCλ Regulate ALDH1-positive Breast Cancer Stem Cell Survival

Hitomi Motomura; Shoma Tamori; Masa-Aki Yatani; Ayano Namiki; Chotaro Onaga; Ayaka Ozaki; Ryoko Takasawa; Yasunari Mano; Tsugumichi Sato; Yasushi Hara; Keiko Sato; Yuyun Xiong; Yohsuke Harada; Takehisa Hanawa; Sei-Ichi Tanuma; Kazunori Sasaki; Shigeo Ohno; Kazunori Akimoto

doi:10.21873/anticanres.15415

GLO 1 and PKCλ Regulate ALDH1-positive Breast Cancer Stem Cell Survival

Anticancer Res. 2021 Dec;41(12):5959-5971. doi: 10.21873/anticanres.15415.

Authors

Hitomi Motomura¹, Shoma Tamori¹, Masa-Aki Yatani¹, Ayano Namiki¹, Chotaro Onaga¹, Ayaka Ozaki¹, Ryoko Takasawa², Yasunari Mano², Tsugumichi Sato², Yasushi Hara³, Keiko Sato⁴, Yuyun Xiong¹, Yohsuke Harada¹, Takehisa Hanawa², Sei-Ichi Tanuma⁵, Kazunori Sasaki⁶, Shigeo Ohno⁶, Kazunori Akimoto⁷

Affiliations

¹ Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
² Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan.
³ Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.
⁴ Department of Information Sciences, Faculty of Sciences and Technology, Tokyo University of Science, Chiba, Japan.
⁵ Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Chiba, Japan.
⁶ Department of Cancer Biology, Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan.
⁷ Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan; akimoto@rs.tus.ac.jp.

PMID: 34848450
DOI: 10.21873/anticanres.15415

Abstract

Background/aim: We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs).

Materials and methods: Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1^high cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined.

Results: GLO 1^high, PKCλ^high, and ALDH1A3^high tumors were enriched in stage I/II/III/IV samples, associated with the HER2 and TNBC subtypes according to receptor status, and associated with the HER2-enriched and basal-like subtypes according to PAM50. Inhibition of either GLO 1 (TLSC702) or PKCλ (ANF) suppressed tumor-sphere formation and enhanced death in ALDH1^high cells. TLSC702 also effectively inhibited tumor-sphere formation and induced death in PKCλ knockout ALDH1^high cells.

Conclusion: GLO 1 and PKCλ are important for the survival of ALDH1-positive breast CSCs, and may represent potential therapeutic targets for the treatment of ALDH1-positive breast CSCs.

Keywords: ALDH1A3; Cancer stem cell; GLO 1; PKCλ; breast cancer.

MeSH terms

Aldehyde Dehydrogenase 1 Family / genetics
Aldehyde Dehydrogenase 1 Family / metabolism*
Biomarkers, Tumor
Breast Neoplasms / etiology
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Survival
Female
Flow Cytometry
Gene Expression Profiling
Humans
Isoenzymes / metabolism*
Lactoylglutathione Lyase / metabolism*
Neoplasm Staging
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Protein Kinase C / metabolism*
Transcriptome

Substances

Biomarkers, Tumor
Isoenzymes
Aldehyde Dehydrogenase 1 Family
Protein Kinase C
protein kinase C lambda
GLO1 protein, human
Lactoylglutathione Lyase