Format

Send to

Choose Destination
Cancer Sci. 2019 Jul 6. doi: 10.1111/cas.14124. [Epub ahead of print]

Effects of metformin and phenformin on apoptosis and epithelial-mesenchymal transition in chemoresistant rectal cancer.

Author information

1
Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Science, Seoul, Korea.
2
Laboratory of Experimental Pathology, Department of Pathology, Korea Institute of Radiological & Medical Science, Seoul, Korea.
3
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.

Abstract

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling.

KEYWORDS:

chemoresistant rectal cancer; metformin; phenformin; phosphorylated-signal transducer and activator of transcription 3 (Ser-727); transforming growth factor β receptor type 2

PMID:
31278880
DOI:
10.1111/cas.14124
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center