Phloretin Overcomes Sorafenib Resistance in Hepatocellular Carcinoma Through Targeting SHP‐1‐and STAT3 Pathways

Abstract

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer death worldwide. Sorafenib (Sor), a tyrosine kinase inhibitor, is first targeted drug approved for HCC. Although, Sor prolongs survival time with limited side effects, many HCC patients become resistant to Sor. Modulation of the Signal Transducer and Activator of Transcription 3 (STAT3) and Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1) pathways are believed to mediate Sor resistance. Thus, identifying effective molecules that could revert the Sor resistance in HCC is a need. Among these promising molecules, Phloretin (PH), a dihydrochalcone flavonoid found in fruit, leaves, and roots of apple tree, possesses anticancer, antitumor, and hepatoprotective effects. However, the effects and potential mechanisms of PH remain elusive.To test our objectives, several HCC cells were tested in vitro for sensitivity to PH, Sor or both and the apoptosis, signal transduction and phosphatase activity were analyzed. The direct role of SHP‐1 was determined using chemical inhibitor and genetic SHP‐1 siRNA knock down. In vivo studies were conducted using Sor‐sensitive and ‐resistant HepG2 and Huh7 xenografts. The animal studies were conducted in conformance with the FASEB Statement of Principles for the use of animals in research and education.The present results showed that PH inhibited cell growth and induced apoptosis in HCC cells by upregulating SHP‐1 expression and downregulating STAT3 activity. PH activated SHP‐1 by disruption of auto‐inhibition of SHP‐1, leading to reduced p‐STAT3Tyr705 level. Inhibiting SHP‐1 expression and activity using specific inhibitor, PTP inhibitor III, or siRNA upregulates p‐STAT3 and counteracted the anti‐proliferative activity of PH. Furthermore, PH induced apoptosis in two Sor‐resistant HCC cell lines and attenuated STAT3‐dependent Sor resistance in HCCs. PH markedly inhibited tumor growth in both Sor‐sensitive and Sor‐resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis.In conclusion, the current data demonstrated that PH inhibits STAT3 activity in Sor‐sensitive and ‐resistant HCCs via SHP‐1–dependent mechanism (Fig. 1). Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a novel targeted therapy for further clinical investigations.Support or Funding InformationQatar University, Qatar National Library, and King Saud UniversityGraphical abstractFigure 1