3,3′-Diindolylmethane Enhances Fluorouracil Sensitivity via Inhibition of Pyrimidine Metabolism in Colorectal Cancer
Jieping Zhang,
Shaomin Zou,
Yijing Zhang,
Ziqing Yang,
Wencong Wang,
Manqi Meng,
Junyan Feng,
Peng Zhang,
Lishi Xiao,
Mong-Hong Lee,
Lekun Fang
Affiliations
Jieping Zhang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Shaomin Zou
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Yijing Zhang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Ziqing Yang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Wencong Wang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Manqi Meng
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Junyan Feng
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Peng Zhang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Lishi Xiao
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Mong-Hong Lee
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Lekun Fang
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
Chemoresistance limits treatment outcomes in colorectal cancer (CRC) patients. A dimeric metabolite of indole-3-carbinol, 3,3′-diindolylmethane (DIM) is abundant in cruciferous vegetables and has shown anticancer efficacy. The role of DIM in regulating chemosensitivity in CRC remains unknown. In this study, we demonstrated that DIM treatment inhibits the malignant progression of CRC. RNA sequencing indicated that pyrimidine synthesis genes are attenuated by DIM treatment. Stable 13C-labeled glucose tracing revealed that DIM inhibits de novo pyrimidine biosynthesis in CRC. DIM increases 5-FU cytotoxicity in CRC via regulation of the expression of pyrimidine metabolism-related genes. DIM synergizes with 5-FU to enhance its inhibitory effects on CRC both in vivo and in vitro. Our results suggest that DIM improves the therapeutic outcomes of FU-based chemotherapy in CRCs by inhibiting pyrimidine metabolism, identifying a new strategy for clinical therapy.
