OBJECTIVE: Metformin, an antidiabetic drug, inhibits the endometrial cancer cell 
growth in vivo by improving the insulin resistance; however, its mechanism of 
action is not completely understood. Protein phosphatase 2A (PP2A) is a 
serine/threonine phosphatase associated with insulin resistance and type 2 
diabetes, and its inhibition restores the insulin resistance. This study 
investigated the antitumor effect of metformin on endometrial cancer with a 
focus on PP2A.
METHODS: Metformin (1,500-2,250 mg/day) was preoperatively administered to 
patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A 
regulatory subunits, 4 (PPP2R4) and B (PP2A-B), was evaluated using real-time 
polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) using paired 
specimens obtained before and after metformin treatment. The effect of PPP2R4 
inhibition with small interfering RNA was evaluated in the endometrial cancer 
cell lines HEC265 and HEC1B. P values of < .05 were considered statistically 
significant.
RESULTS: Preoperative metformin treatment significantly reduced the expression 
of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as 
determined using RT-PCR, in the patients with endometrial cancer. However, 
metformin could not directly alter the PPP2R4 mRNA levels in the endometrial 
cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and 
induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells.
CONCLUSIONS: Downregulation of the PP2A-B subunit, including PPP2R4, is an 
important indirect target of metformin. Inhibition of PP2A may be an option for 
the treatment of endometrial cancer patients with insulin resistance.
TRIAL REGISTRATION: This trial is registered with UMIN-CTR (number 
UMIN000004852).