Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

Xiaoli Li; Guoli Wang; Xiaolin Zhou; Huijie Zhao; Xiaojie Chen; Qixiao Cui; Minjing Li; Xihang Gao; Xiaoyu Wei; Lei Ye; Defang Li; Pan Hong

doi:10.1002/ptr.7943

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT

Phytother Res. 2023 Oct;37(10):4740-4754. doi: 10.1002/ptr.7943. Epub 2023 Aug 9.

Authors

Xiaoli Li^{1

2}, Guoli Wang^{1

2}, Xiaolin Zhou^{1

2}, Huijie Zhao^{1

2}, Xiaojie Chen^{1

2}, Qixiao Cui^{1

2

3}, Minjing Li^{1

2}, Xihang Gao^{1

2}, Xiaoyu Wei^{1

2}, Lei Ye^{1

2}, Defang Li^{1

2}, Pan Hong^{1

2}

Affiliations

¹ Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
² Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
³ College of Stomatology, Binzhou Medical University, Yantai, Shandong, People's Republic of China.

PMID: 37559472
DOI: 10.1002/ptr.7943

Abstract

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.

Keywords: AKT/mTOR; HSP90; gastric cancer; picropodophyllin.

Abstract

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