Journal Article

ABCG2 expression is related to low 5-ALA photodynamic diagnosis (PDD) efficacy and cancer stem cell phenotype, and suppression of ABCG2 improves the efficacy of PDD

Nakatsugawa, Munehide, Tsukahara, Tomohide, Li, Liming, Shichinohe, Toshiaki, Ebihara, Yuma, Saito, Takuma, Kawai, Noriko, Kanaseki, Takayuki, Torigoe, Toshihiko, Saito, Takahiro, Murai, Aiko, Shirosaki, Tomohide, Hirohashi, Yoshihiko, Hirano, Satoshi, Kubo, Terufumi

2019

Overview

Photodynamic diagnosis/therapy (PDD/PDT) are novel modalities for the diagnosis and treatment of cancer. The photosensitizer protoporphyrin IX is metabolized from 5-aminolevulinic acid (5-ALA) intracellularly, and PDD/PDT using 5-ALA have been approved in dermatologic malignancies and gliomas. However, the molecular mechanism that defines the efficacy of PDD/PDT is unknown. In this study, we analyzed the functions of ATP-binding cassette (ABC) transporters in PDD using 5-ALA. Most of the human gastrointestinal cancer line cells examined showed a homogenous staining pattern with 5-ALA, except for the pancreatic cancer line PANC-1, which showed heterogeneous staining. To analyze this heterogeneous staining pattern, single cell clones were established from PANC-1 cells and the expression of ABC transporters was assessed. Among the ABC transporter genes examined, ABCG2 showed an inverse correlation with the rate of 5-ALA-positive staining. PANC-1 clone #2 cells showed the highest level of ABCG2 expression and the lowest level of 5-ALA staining, with only a 0.6% positive rate. Knockdown of the ABCG2 gene by small interfering RNAs increased the positive rate of 5-ALA staining in PANC-1 wild-type and clone cells. Interestingly, PANC-1 clone #2 cells showed the high sphere-forming ability and tumor-formation ability, indicating that the cells contained high numbers of cancer stem cells (CSCs). Knockdown or inhibition of ABCG2 increased the rate of 5-ALA staining, but did not decrease sphere-forming ability. These results indicate that gastrointestinal cancer cell lines expressing high levels of ABCG2 are enriched with CSCs and show low rates of 5-ALA staining, but 5-ALA staining rates can be improved by inhibition of ABCG2.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ABC transporter / ABCG2 gene / Aminolevulinic acid / Aminolevulinic Acid - pharmacology / Animal genetic engineering / Animals / ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics / Biology and Life Sciences / Biomedical research / Breast cancer / Cancer / Cancer therapies / Cancer treatment / Care and treatment / Cell Line, Tumor / Chemotherapy / Cloning / Cytoplasm / Diagnosis / Diketopiperazines - pharmacology / Drug resistance / Effectiveness / Evaluation / Female / Gastric cancer / Gastrointestinal cancer / Gastrointestinal Neoplasms - diagnosis / Gastrointestinal Neoplasms - genetics / Gastrointestinal Neoplasms - metabolism / Gastrointestinal Neoplasms - therapy / Gene expression / Gene Expression Regulation, Neoplastic / Genes / Glioma / Gliomas / Health aspects / Heterocyclic Compounds, 4 or More Rings - pharmacology / Humans / Influence / Inhibition / Levels / Lymphatic system / Medical diagnosis / Medical research / Medicine / Medicine and Health Sciences / Metastasis / Mice / Mitochondria / Neoplasm Proteins - genetics / Neoplasm Transplantation / Neoplastic Stem Cells - metabolism / Novels / Pancreatic cancer / Pathology / Penicillin / Phenotypes / Photochemotherapy / Photodynamic therapy / Photosensitizing Agents - pharmacology / Prostate / Protoporphyrin / Protoporphyrin IX / Protoporphyrins - metabolism / Psychics / Research and Analysis Methods / Single-Cell Analysis / Staining / Stem cells / Stomach cancer / Surgery / Transport proteins / Tumor cell lines / Tumors / University graduates / Up-Regulation