Calcitriol exerts an anti‐tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response

Autor: Takatsune Shimizu, Akihiro Muto, Yumi Fukuchi, Walied A. Kamel, Sayaka Yamaguchi-Iwai, Hideyuki Saya
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_specialty
Calcitriol
Cell Survival
Antineoplastic Agents
Bone Neoplasms
vitamin D
Endoplasmic Reticulum
03 medical and health sciences
Cell
Molecular
and Stem Cell Biology
Downregulation and upregulation
Cell Line
Tumor
Internal medicine
polycyclic compounds
Animals
Humans
Medicine
Viability assay
Cell Proliferation
Osteosarcoma
business.industry
Cell growth
Endoplasmic reticulum
Original Articles
General Medicine
Cell cycle
Endoplasmic Reticulum Stress
medicine.disease
Xenograft Model Antitumor Assays
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
Oncology
Cancer research
Unfolded protein response
Female
Original Article
cell cycle
lipids (amino acids
peptides
and proteins)
Reactive Oxygen Species
business
Injections
Intraperitoneal
medicine.drug
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)‐approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin D1, activation of p38 MAPK, and intracellular production of reactive oxygen species (ROS). Knockdown of Atf4 or Ddit3 restored cell viability after calcitriol treatment, indicating that the ER stress response was indeed responsible for the anti‐proliferative effect in AXT cells. Notably, the ER stress response was induced to a lesser extent in human osteosarcoma than in AXT cells, consistent with the weaker suppressive effect on cell growth in the human cells. Thus, the magnitude of ER stress induced by calcitriol might be an index of its anti‐osteosarcoma effect. Although mice treated with calcitriol exhibited weight loss and elevated serum calcium levels, a single dose was sufficient to decrease osteosarcoma tumor size in vivo. Our findings suggest that calcitriol holds therapeutic potential for treatment of osteosarcoma, assuming that techniques to diminish its toxicity could be established. In addition, our results show that calcitriol could still be safely administered to osteosarcoma patients for its original purposes, including treatment of osteoporosis.
Databáze: OpenAIRE
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