Abstract
Hedgehog (Hh) signaling is activated in numerous malignant tumors, but its role in human colorectal cancer remains uncertain. Celecoxib, a selective cyclooxygenase-2 inhibitor, has been shown to exhibit chemoprevention in colorectal cancer, however, the effects of celecoxib on Hh signaling remain unknown. The current study presents an evaluation of Hh signaling in colon cancer cell lines and the effects of celecoxib in vitro. Active Hh signaling was observed in LoVo and HT-29 cells, with particularly high levels in the LoVo cells. However, Hh signaling activity was absent in HCT-116 cells. Quantitative polymerase chain reaction indicated that the expression of Hh receptor patched homolog 1 (PTCH1) was absent in the LoVo cells, but that they exhibited high levels of glioma-associated oncogene homolog-1 (GLI1) expression, while high expression levels of PTCH1 and low expression levels of smoothened (SMO) and GLI1 were observed in the HCT-116 cells. The HCT-116 cells were extremely sensitive to celecoxib, whereas the LoVo cells were resistant to the anticancer effect of the drug. Celecoxib downregulated the expression of GLI1 in the HCT-116 and HT-29 cells, but did not change the expression of GLI1 in the LoVo cells. The results presented in this study indicated that the anticancer effect of celecoxib is selective in colon cancer cells; celecoxib may target cancer cells via the SMO-independent modulation of GLI1 activity, and Hh signaling may be significant in maintaining the malignant state of LoVo cells. These findings may aid in improving our understanding of the carcinogenesis of colon cancer and the development of novel approaches for the targeted therapy of this disease.
Highlights
Colorectal cancer is one of the most common malignancies worldwide, with >1,000,000 cases reported annually [1]
Aberrant Hh signaling is indicated to be involved in endodermally‐derived human cancers that account for 25% of human cancer-related mortalities [19], the role of Hh signaling in human colorectal cancers is not fully understood [6,7], and several studies have indicated that Hh signaling is inactive in colorectal cancer [8,9,10]
The results of the current study demonstrated that the absent expression of patched homolog 1 (PTCH1) in LoVo cells is associated with epigenetic changes, as the expression of PTCH1 was present in these cells following treatment with cyclopamine or celecoxib
Summary
Colorectal cancer is one of the most common malignancies worldwide, with >1,000,000 cases reported annually [1]. Several developmental signaling pathways that are involved in the carcinogenesis of colorectal cancer, including the Wnt/β‐catenin [2], TGF‐β/Smad [3] Notch [4] and receptor tyrosine kinase [5] pathways, have been widely investigated. Canonical Hh signaling predominantly consists of Hh, the Hh receptor, patched homolog 1 (PTCH1), the intermediary signaling molecule, smoothened (SMO), and the transcription factor, GLI. In the absence of Hh, PTCH1 interacts with SMO and inhibits its activity, while GLI is degraded to the repressor form, which results in the transcriptional inhibition of Hh target genes. The active SMO affects the expression of GLI proteins, which may enter the nucleus and regulate the expression of the Hh target genes (including PTCH1, GLI, Wnt, c‐MYC and CCND1) in responding cells [12,13]. Cyclopamine, a specific inhibitor of SMO [16], is currently under investigation in anticancer studies
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