6-Shogaol Antagonizes the Adipocyte-Conditioned Medium-Initiated 5-Fluorouracil Resistance in Human Colorectal Cancer Cells through Controlling the SREBP-1 Level.

Ko-Chao Lee,Cheng-Nan Chen,Chia-Kung Yen,Kuen-Lin Wu,Shun-Fu Chang,Wen-Shih Huang

doi:10.3390/life11101067

Abstract

The resistance of colorectal cancer (CRC) to chemotherapy, e.g., 5-fluorouracil (5-FU), is an impediment to successful cancer treatment. Although many mechanisms have been proposed to explain the occurrence of resistance, little is known concerning the role of the adipocyte-containing microenvironment of CRC. Accumulating data have proposed that the combined therapy of clinical drugs with ginger derivatives, e.g., 6-shogaol, might improve resistance development. In the present study, we examined the effect of adipocyte-conditioned medium (ACM) on 5-FU-treated CRC cells (human DLD-1 and SW480 cells) and further examined the possible antagonized role of 6-shogaol in this situation. It was shown that the level of sterol-regulatory element-binding protein-1 (SREBP-1), a critical transcription factor involved in lipid synthesis and metabolism, would be upregulated through Akt and p70S6K signaling pathways while CRC cells are cultured in ACM, which subsequently decreases the cell sensitivity to 5-FU cytotoxicity. Moreover, our results also demonstrated the antagonized role of 6-shogaol in attenuating the ACM effects on CRC cells through activating AMPK signaling. Overall, the present study elucidated the role of adipocyte-containing microenvironment in 5-FU resistance development of CRC through controlling the SREBP-1 level and further enhanced the concept of clinical application of 6-shogaol and AMPK signaling in CRC therapy.

Highlights

Colorectal cancer (CRC) still accounts for the most common cancer types and cancerassociated deaths in the world [1,2]
Results and SW480 CRC cells were cultured in control medium (CM) or adipocyte-conditional medium (ACM) for 8 h and were kept as controls or treated with 5-FU (2.5, 5, and 10 medium (ACM) for 8 h and were kept as controls or treated with 5-FU (2.5, 5, and μM) for 24 h
It was shown that 5-FU dose-dependently induces the cell death of both types of CRC cells cultured in that 5-FU dose-dependently induces the cell death of both types of CRC cells cultured in both CM and adipocyte-conditioned medium (ACM) (Figure 1A)

Summary

Introduction

Colorectal cancer (CRC) still accounts for the most common cancer types and cancerassociated deaths in the world [1,2]. The CRC screening has been promoted and conducted in many countries for more than 10 years, the incidence is still elevated annually. The rate of CRC patients whose age is below 50 years increased rapidly in the past decade [1,2]. It has long been indicated that a poor diet with excess calorie intake is still the major cause of CRC development. In spite of the improvement and advance of the therapeutic strategy, including chemotherapy and radiation, one of the most challenges of CRC has been the occurrence of resistance [3]. A more detailed and precise study of resistance development about biomarker screen and the underlying mechanism has been thought to be necessary and urgent

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