Abstract
Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.
Highlights
Colorectal cancer (CRC), both the third most common form of cancer and the third leading cause of cancerrelated death worldwide, can attribute its effect in part to the metastases of its parent tumor [1]
Before investigating the effect of combined treatment with metformin and tumor necrosis factor-related apoptosisinducing ligand (TRAIL) on viability of colorectal cancer (CRC) cells, we evaluated whether metformin alone induces cell death
These results suggest that the sensitizing regimen of metformin plus TRAIL may be selectively toxic to CRC cells
Summary
Colorectal cancer (CRC), both the third most common form of cancer and the third leading cause of cancerrelated death worldwide, can attribute its effect in part to the metastases of its parent tumor [1]. Numerous studies have recently made remarkable advances in the search for a cure for metastatic CRC. Median overall survival was increased by nearly a factor of two to 20 months when monoclonal antibody therapies such as cetuximab and bevacizumab were used [3,4,5]. Despite these advances, there remains a lack of effective drugs to improve overall survival in patients with CRC. Development of new therapies for metastatic CRC is urgent
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