Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the
endoplasmic reticulum stress response
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Shimizu T
; Kamel WA
; Yamaguchi-Iwai S
; Fukuchi Y
; Muto A
; Saya H
Cancer Sci
2017[Sep]; 108
(9
): 1793-1802
PMID28643892
show ga
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.
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