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Tanshinones induce tumor cell apoptosis via directly targeting FHIT

Xianglian Zhou1, Yuting Pan1, Yue Wang1

  • 1Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Scientific Reports
|June 10, 2021
PubMed

Insights

Tanshinone compounds, like sodium tanshinone IIA sulfonate (STS), directly bind to and inhibit the fragile histidine triad (FHIT) protein. This interaction is key to the anti-cancer effects of tanshinones, particularly in colorectal cancer cells.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Biochemistry

Background:

  • Liposoluble tanshinones from Salvia miltiorrhiza are studied for anti-cancer properties.
  • The precise molecular mechanisms of tanshinone anti-cancer activity remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of anti-cancer tanshinones.
  • To identify direct protein targets of tanshinone derivatives.

Main Methods:

  • Identified direct binding between sodium tanshinone IIA sulfonate (STS) and fragile histidine triad (FHIT) protein using binding assays.
  • Assessed the inhibitory effect of STS on FHIT's diadenosine triphosphate (Ap3A) hydrolase activity.
  • Investigated binding affinities of STS to other HIT family proteins.
  • Examined the effect of FHIT depletion on tanshinone-induced apoptosis in colorectal cancer cells.

Main Results:

  • STS directly binds to FHIT with a Kd of 268.4 nM.
  • STS inhibits FHIT's Ap3A hydrolase activity (IC50 = 2.2 µM) by competing for the substrate-binding site.
  • Other tanshinones (TSA, TanI, CST) showed similar inhibitory activity.
  • FHIT depletion abrogated the pro-apoptotic effect of TSA in HCT116 colorectal cancer cells.

Conclusions:

  • Fragile histidine triad (FHIT) is a direct molecular target of tanshinone compounds.
  • Inhibition of FHIT activity by tanshinones contributes to their anti-cancer effects.
  • This study provides molecular insight into the anti-cancer mechanisms of Salvia miltiorrhiza-derived tanshinones.

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