Metformin selectively inhibits metastatic colorectal cancer with the KRAS mutation by intracellular accumulation through silencing MATE1.

Abstract

Metastatic colorectal cancer (mCRC) patients have poor overall survival despite using irinotecan- or oxaliplatin-based chemotherapy combined with anti-EGFR (epidermal growth factor receptor) drugs, especially those with the oncogene mutation of KRAS Metformin has been reported as a potentially novel antitumor agent in many experiments, but its therapeutic activity is discrepant and controversial so far. Inspiringly, the median survival time for KRAS-mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. In contrast, metformin could not improve the survival of mCRC patients with wild-type KRAS Interestingly, metformin is preferentially accumulated in KRAS-mutation mCRC cells, but not wild-type ones, in both primary cell cultures and patient-derived xenografts, which is in agreement with its tremendous effect in KRAS-mutation mCRC. Mechanistically, the mutated KRAS oncoprotein hypermethylates and silences the expression of multidrug and toxic compound extrusion 1 (MATE1), a specific pump that expels metformin from the tumor cells by up-regulating DNA methyltransferase 1 (DNMT1). Our findings provide evidence that KRAS-mutation mCRC patients benefit from metformin treatment and targeting MATE1 may provide a strategy to improve the anticancer response of metformin.

• Authors: Jinye Xie, Liangping Xia, Wei Xiang, Wenzhuo He, Haofan Yin, Fang Wang, Tianxiao Gao, Weiwei Qi, Zhonghan Yang, Xia Yang, Ti Zhou, Guoquan Gao
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 23 Pg. 13012-13022 (06 09 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32444490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• KRAS protein, human
• Organic Cation Transport Proteins
• SLC47A1 protein, human
• Metformin
• DNA (Cytosine-5-)-Methyltransferase 1
• DNMT1 protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Colorectal Neoplasms (drug therapy, genetics, mortality, pathology)
• DNA (Cytosine-5-)-Methyltransferase 1 (metabolism)
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Metformin (pharmacology, therapeutic use)
• Mice
• Middle Aged
• Organic Cation Transport Proteins (metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Xenograft Model Antitumor Assays