Metformin induces TPC-1 cell apoptosis through endoplasmic reticulum stress-associated pathways in vitro and in vivo

Int J Oncol. 2019 Jul;55(1):331-339. doi: 10.3892/ijo.2019.4820. Epub 2019 May 31.

Abstract

Thyroid cancer is among the most common types of malignant tumor of the endocrine system. The role of metformin in the inhibition of cancer cell proliferation and induction of apoptosis is widely accepted. The present study explored the effect and the underlying mechanisms of metformin on human thyroid cancer TPC‑1 cells. Following treatment of TPC‑1 cells with different concentrations of metformin, cell proliferation and apoptosis were analyzed by cell counting kit‑8 (CCK‑8) assay and flow cytometry, respectively. Reverse transcription‑quantitative PCR and western blotting were used to detect alterations in the mRNA and protein expression levels, respectively, for heat shock protein family A member 5 (HSPA5, also known as Bip), DNA damage‑inducible transcript 3 (DDIT3, also known as CHOP) and caspase‑12. The results demonstrated that treatment with metformin inhibited proliferation and induced apoptosis in a concentration and time‑dependent manner. In addition, treatment with metformin increased the expression of Bip, CHOP and caspase‑12 in vitro, activating endoplasmic reticulum (ER) stress. Thapsigargin treatment enhanced the apoptosis induced by metformin. Inhibition of ER stress by 4‑phenylbutyrate reversed the metformin‑induced apoptosis. Finally, treatment with metformin inhibited thyroid cancer growth and increased the expression of Bip and CHOP in a TPC‑1 cell xenograft model. These results indicated that metformin increased the apoptotic rate of thyroid cancer cells via ER stress‑associated mechanisms.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Humans
  • Male
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Thyroid Cancer, Papillary / drug therapy*
  • Thyroid Cancer, Papillary / pathology
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / pathology

Substances

  • Metformin