Celecoxib-Induced Cytotoxic Effect Is Potentiated by Inhibition of Autophagy in Human Urothelial Carcinoma Cells

Abstract

Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC.

Indomethacin suppresses LAMP-2 expression and induces lipophagy and lipoapoptosis in rat enterocytes via the ER stress pathway

“…Moreover, the suppressed autophagy by indomethacin in LD-laden enterocytes may interfere with ulcer healing [22,61]. The data from the current study are supported by a recent publication showing that inhibition of autophagy by 3-MA or ATG7 knockdown decreased viability and increased apoptosis in celecoxib-treated urothelial carcinoma cells [62]. However, there is need for further research regarding toxicity of NSAIDs in animal models of autophagy gene knockout.…”

Autophagy: novel applications of nonsteroidal anti‐inflammatory drugs for primary cancer

“…There are more than 20 proteins involved in the autophagy pathway downstream of mTOR. Research has shown that the levels of the conjugated Atg5‐Atg12 protein increase significantly after treatment with celecoxib, meloxicam, or OSU‐03012 . OSU‐03012 is a derivative of celecoxib, a COX‐2 inhibitor, with anticancer activity that has been shown to induce the death of various types of cancer cells .…”

“…The prodeath or prosurvival nature of the response may be related to tumor type, stage, and the ability of the tumor cells to sustain themselves. Some studies have reported that inhibition of autophagy enhances cellular apoptosis .…”

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

“…The CPS-induced autophagy is evoked at the same time with cell death and involves the DNA repair system functioning as a pathway that counteracts the CPS-induced apoptosis prolonging cancer cell survival [11, 12]. Moreover, several reports demonstrated that autophagy inhibition sensitizes BC cells to chemotherapy, indicating that in BC, targeting autophagy may be an effective therapeutic strategy to overcome drug resistance [13]. …”