Cardamonin induces apoptosis by suppressing STAT3 signaling pathway in glioblastoma stem cells
Ning Wu1, Jia Liu2, Xiangzhong Zhao3
1Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China.
Abstract:
Glioblastoma stem cells (GSCs) are the initiating cells in glioblastoma multiforme (GBM) and contribute to the resistance of GBM to chemotherapy and radiation. In the present study, we investigated the effects of cardamonin (3,4,2,4-tetrahydroxychalcone) on the self-renewal and apoptosis of GSCs, and if its action is associated with signal transducer and activator of transcription 3 (STAT3) pathway. CD133(+) GSCs, a kind of GSCs line, was established from human glioblastoma tissues. Cardamonin inhibited the proliferation and induced apoptosis in CD133+ GSCs. The proapoptotic effects of temozolomide (TMZ) were further enhanced by cardamonin in CD133+ GSCs and U87 cells in vitro. For in vivo study, injection of 5 × 10(5) cells of CD133+ GSCs subcutaneously (s.c.) into nude mice, 100 % of large tumors were developed within 8 weeks in all mice; in contrast, only one out of five mice developed a small tumor when 5 × 10(5) cells of CD133(-) GMBs cells were injected. Cardamonin also inhibited STAT3 activation by luciferase assay and suppressed the expression of the downstream genes of STAT3, such as Bcl-XL, Bcl-2, Mcl-1, survivin, and VEGF. Furthermore, cardamonin locked nuclear translocation and dimerization of STAT3 in CD133(+) GSCs. Docking analysis confirmed that cardamonin molecule was successfully docked into the active sites of STAT3 with a highly favorable binding energy of -10.78 kcal/mol. The study provides evidence that cardamonin is a novel inhibitor of STAT3 and has the potential to be developed as a new anticancer agent targeting GSCs. This study also reveals that targeting STAT3 signal pathway is an important strategy for the treatment of human GBM.
Insights
Cardamonin effectively inhibits glioblastoma stem cells (GSCs) proliferation and induces apoptosis. This natural compound targets the STAT3 pathway, showing potential as a novel anticancer agent for glioblastoma multiforme (GBM).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma stem cells (GSCs) drive glioblastoma multiforme (GBM) and confer resistance to therapies.
- The signal transducer and activator of transcription 3 (STAT3) pathway is implicated in GSC self-renewal and survival.
Purpose of the Study:
- To investigate the effects of cardamonin on GSC self-renewal and apoptosis.
- To determine if cardamonin's action involves the STAT3 signaling pathway.
Main Methods:
- Cardamonin treatment of CD133(+) GSCs and U87 cells in vitro.
- In vivo studies using GSC xenografts in nude mice.
- Luciferase assays to assess STAT3 activation and downstream gene expression.
- Molecular docking analysis of cardamonin with STAT3.
Main Results:
- Cardamonin inhibited GSC proliferation and induced apoptosis.
- Cardamonin enhanced the efficacy of temozolomide (TMZ) against GSCs.
- In vivo, cardamonin suppressed tumor growth from GSCs.
- Cardamonin inhibited STAT3 activation, nuclear translocation, and dimerization, suppressing key downstream genes (Bcl-XL, Bcl-2, Mcl-1, survivin, VEGF).
- Molecular docking confirmed cardamonin binds to STAT3 active sites.
Conclusions:
- Cardamonin is a novel STAT3 inhibitor with potent anticancer activity against GSCs.
- Cardamonin demonstrates potential as a therapeutic agent for glioblastoma.
- Targeting the STAT3 pathway is a promising strategy for GBM treatment.
