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28 March 2017 : Laboratory Research  

Targeting Smoothened Sensitizes Gastric Cancer to Chemotherapy in Experimental Models

Huifa Ma1ABCDEFG*, Yongsheng Tian1ABCEF, Xiangyang Yu2BCDEF

DOI: 10.12659/MSM.903012

Med Sci Monit 2017; 23:1493-1500

Abstract

BACKGROUND: The Hedgehog pathway receptor smoothened (SMO) has critical roles in tumor progression. However, whether SMO is a key factor regulating gastric cancer chemotherapy resistance is unknown.

MATERIAL AND METHODS: We investigated the potential functions of SMO in inducing gastric cancer paclitaxel resistance in clinical samples, gastric cancer cell lines (424GC and AGS), and subcutaneous syngeneic mouse models.

RESULTS: We found high SMO expression in paclitaxel-resistant gastric cancer clinical samples. Paclitaxel gastric cancer cells had higher SMO expression than in drug-sensitive cells. Upregulating SMO expression induced paclitaxel resistance in gastric cells lines via enhancing cell proliferation and inhibiting apoptosis. The combination of IPI-926, an inhibitor of SMO, with paclitaxel decreased cell viability of paclitaxel-resistant gastric cancer cells in vitro and controlled tumor growth in animal models.

CONCLUSIONS: The Hedgehog pathway receptor SMO is an important regulator of gastric cancer paclitaxel resistance and could be a target for sensitizing paclitaxel-resistant tumors.

Keywords: Drug Resistance, Hedgehog Proteins, Stomach Neoplasms

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Medical Science Monitor Basic Research eISSN: 2325-4416
Medical Science Monitor Basic Research eISSN: 2325-4416