Hydroxymethylglutaryl-Coenzyme A Synthase 2 Expression Is Associated With Chemoradiotherapy Responses in Colorectal Cancer

Abstract

BACKGROUND: Preoperative chemoradiotherapy has become a standard treatment modality for locally advanced rectal cancer. Favorable long-term outcomes have been reported for patients with good responses to chemoradiotherapy. Therefore, predictive factors for chemoradiotherapy responses can be useful for their applicability to risk-adaptive therapy in patients with colorectal cancer. OBJECTIVE: The aim of this study was to investigate whether hydroxymethylglutaryl-coenzyme A synthase 2, a key enzyme in ketogenesis, is associated with the responses of colorectal cancer cells to chemoradiotherapy. DESIGN: Hydroxymethylglutaryl-coenzyme A synthase 2 was identified by a 2-dimensional gel electrophoresis-based proteome analysis. It was analyzed in 12 colorectal cancer cells for associations with radiation or 5-fluorouracil susceptibility by Western blotting, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium Bromide assay, and small interfering RNA transfection. Then, tumor tissues obtained from 45 patients with rectal cancer before chemoradiotherapy were analyzed by Western blotting for associations with chemoradiotherapy responses. RESULTS: Expression of hydroxymethylglutaryl-coenzyme A synthase 2 was significantly correlated with intrinsic radiation resistance of 12 cancer cells. Hydroxymethylglutaryl-coenzyme A synthase 2 expression was significantly affected by treatment with either 5-fluorouracil or radiation depending on cell types. The artificial suppression of hydroxymethylglutaryl-coenzyme A synthase 2 did not result in the change of chemoradiation susceptibility in colorectal cancer cells. Nevertheless, in multivariate analyses, hydroxymethylglutaryl-coenzyme A synthase 2 expression in rectal cancer tissues was shown to be a significant predictive factor for chemoradiotherapy responses, as evaluated in terms of tumor regression grade and downstaging. LIMITATIONS: Overall findings in vitro showed that the expression level of hydroxymethylglutaryl-coenzyme A synthase 2 was highly variable depending on colon cancer cell types, and it cannot directly affect on chemoradiotherapy responses. The molecular mechanism underpinning the association between hydroxymethylglutaryl-coenzyme A synthase expression and chemoradiotherapy responses needs to be elucidated through future research. CONCLUSIONS: Hydroxymethylglutaryl-coenzyme A synthase 2 was associated with the effects of chemoradiotherapy on human colorectal cancer cells. Pretreatment levels of hydroxymethylglutaryl-coenzyme A synthase 2 in rectal cancer may be useful in predicting the responses to chemoradiotherapy.