Visfatin and Resveratrol Differentially Regulate the Expression of Thymidylate Synthase to Control the Sensitivity of Human Colorectal Cancer Cells to Capecitabine Cytotoxicity

Colorectal cancer (CRC) is a highly lethal malignant cancer. Capecitabine, a 5-fluororacil (5-FU) derivate, is its first-line drug, but the resistance of CRC to capecitabine is still the most challenging factor for curing patients. It has been suggested that thymidylate synthase (TYMS) level might affect the capecitabine efficacy in CRC patients, but the mechanism still needs more elucidation. Obesity is a risk factor for CRC. Recently, a correlation between serum visfatin, an obesity-elicited adipokine, and CRC development has been found. Thus, the aim of present study is to examine the visfatin capacity in TYMS expression and in the development of capecitabine resistance of CRC. Moreover, an attractive natural component, i.e., resveratrol, has been proposed in anticancer therapy and has hence been examined in the present study to see its potential capacity in the alleviation of CRC resistance. Our results found that visfatin significantly reduces the CRC sensitivity to capecitabine by controlling the TYMS expression via p38 signaling and Sp1 transcription factor. Moreover, resveratrol could significantly alleviate the visfatin effect on capecitabine-treated CRC cells. These results provided new insights to understand the capecitabine susceptibility of CRC under a visfatin-containing environment and a possible therapeutic application of resveratrol in CRC patients with obesity.

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Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in hct116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Molecules ◽

10.3390/molecules26071856 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1856

Author(s):

Yong-Hwi Kang ◽

Jin-Seok Lee ◽

Nam-Hun Lee ◽

Seung-Hyung Kim ◽

Chang-Seob Seo ◽

...

Keyword(s):

Colorectal Cancer ◽

Thymidylate Synthase ◽

Cell Cycle Distribution ◽

Human Colorectal Cancer ◽

Common Cancer ◽

G1 Phase Arrest ◽

Colorectal Cancer Cells ◽

Coptidis Rhizoma ◽

Underlying Mechanisms ◽

Human Colorectal Cancer Cells

Colorectal cancer (CRC) is a malignancy of the colon or rectum. It is ranked as the third most common cancer in both men and women worldwide. Early resection permitted by early detection is the best treatment, and chemotherapy is another main treatment, particularly for patients with advanced CRC. A well-known thymidylate synthase (TS) inhibitor, 5-fluorouracil (5-FU), is frequently prescribed to CRC patients; however, drug resistance is a critical limitation of its clinical application. Based on the hypothesis that Coptidis Rhizoma extract (CRE) can abolish this 5-FU resistance, we explored the efficacy and underlying mechanisms of CRE in 5-FU-resistant (HCT116/R) and parental HCT116 (HCT116/WT) cells. Compared to treatment with 5-FU alone, combination treatment with CRE and 5-FU drastically reduced the viability of HCT116/R cells. The cell cycle distribution assay showed significant induction of the G0/G1 phase arrest by co-treatment with CRE and 5-FU. In addition, the combination of CRE and 5-FU notably suppressed the activity of TS, which was overexpressed in HCT116/R cells, as compared to HCT116/WT cells. Our findings support the potential of CRE as an adjuvant agent against 5-FU-resistant colorectal cancers and indicate that the underlying mechanisms might involve inhibition of TS expression.

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Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

Cancers ◽

10.3390/cancers13050982 ◽

2021 ◽

Vol 13 (5) ◽

pp. 982

Author(s):

Motoki Watanabe ◽

Yasumasa Yamada ◽

Yoichi Kurumida ◽

Tomoshi Kameda ◽

Mamiko Sukeno ◽

...

Keyword(s):

Colorectal Cancer ◽

Thymidylate Synthase ◽

Magnetic Beads ◽

Adenine Nucleotide ◽

Mrna Levels ◽

Lead Compound ◽

Human Colorectal Cancer ◽

Mitochondrial Inner Membrane ◽

Colorectal Cancer Cells ◽

Human Colorectal Cancer Cells

Natural products have numerous bioactivities and are expected to be a resource for potent drugs. However, their direct targets in cells often remain unclear. We found that rabdosianone I, which is a bitter diterpene from an oriental herb for longevity, Isodon japonicus Hara, markedly inhibited the growth of human colorectal cancer cells by downregulating the expression of thymidylate synthase (TS). Next, using rabdosianone I-immobilized nano-magnetic beads, we identified two mitochondrial inner membrane proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as direct targets of rabdosianone I. Consistent with the action of rabdosianone I, the depletion of ANT2 or PHB2 reduced TS expression in a different manner. The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor.

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