mTOR activation is critical for betulin treatment in renal cell carcinoma cells

Biochem Biophys Res Commun. 2017 Jan 22;482(4):1030-1036. doi: 10.1016/j.bbrc.2016.11.153. Epub 2016 Nov 28.

Abstract

Betulin, a natural product isolated from the bark of the birch trees, exhibits multiple anticancer effects. Activation of mTOR signaling pathway has been found in numerous cancers, including renal cell carcinoma (RCC). Here, we attempted to study whether mTOR signaling was essential for betulin to treat RCC. Based on cell survival and colony formation assays, we found that mTOR hyperactive RCC cell line 786-O cells were more sensitive to betulin treatment compared with mTOR-inactive Caki-2 cells. Knockdown of TSC2 in Caki-2 cells had similar results to 786-O cells, and mTOR silencing in 786-O cells rescued the inhibitory effect of betulin, indicating that betulin inhibited RCC cell proliferation in an mTOR-dependent manner. Furthermore, betulin treatment decreases the levels of glucose consumption and lactate production in 786-O cells, while minimal effects were observed in Caki-2 cells. In addition, betulin significantly inhibited the expression of PKM2 and HK2 in 786-O cells. Finally, knockdown of PKM2 or HK2 in 786-O reversed the anti-proliferative effects of betulin, and overexpression of PKM2 or HK2 in Caki-2 cells enhanced the sensitivity to betulin treatment. Taken together, these findings demonstrated the critical role of mTOR activation in RCC cells to betulin treatment, suggesting that betulin might be valuable for targeted therapies in RCC patients with mTOR activation.

Keywords: Betulin; Renal cell carcinoma; mTOR.

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Betula / chemistry
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Enzyme Activation / drug effects*
  • Glycolysis / drug effects
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Membrane Proteins / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / metabolism
  • Triterpenes / chemistry
  • Triterpenes / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Carrier Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • Triterpenes
  • betulin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases