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Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis Through the Mitochondria‑Dependent Apoptosis in Human Gastric Cancer Cells

ABSTRACT: The major treatment strategies for gastric cancer (GC) including surgery, chemotherapy, and molecular-targeted therapy are limited by tumor recurrence and chemoresistance. Isorhamnetin (ISO) derives from the total flavones of Hippophae rhamnoides L. and has been used as potential antitumor medicine in several types of cancer. However, the antitumor effect of ISO on GC cells remains unclear. Here, we investigated the effects of ISO on two types of GC cells and explored its apoptotic mechanisms underlying such effects. The transcriptomic analysis of ISO-treated GC cells enriched multiple targets on cell growth and apoptosis. The CCK-8, colony formation and morphology observation assays demonstrated that ISO treatment significantly inhibited the growth and proliferation of GC cells in time- and dose-dependent manners. In addition, we also found that ISO treatment inhibited cell migration and invasion. Furthermore, ISO increased TUNEL positive apoptotic bodies as well as severe cell apoptosis. Intriguingly, ISO treatment significantly increased the expression of mitochondria-associated Bax/Bcl-2, cytosolic Cytochrome c and activated the cleavage of Caspase-3 and PARP, followed by severe reduction of mitochondrial potential. Moreover, the apoptosis of ISO-treated GC cells was blocked by the specific inhibitor of Caspase-3. Therefore, we demonstrated that ISO could induce apoptosis of GC cells through mitochondria-dependent apoptotic pathway. In summary, we reported for the first time the antitumor function of ISO in GC via intervening apoptosis, indicating a potential application in GC therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204967 | GEO | 2022/05/30

REPOSITORIES: GEO

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Project description:Different types of cell death, including apoptosis, play an important role in the immune defense of arthropods, as infected cells are eliminated, preventing the dissemination of the infectious agent throughout the animal body. The apoptosis can be triggered by two main pathways: the intrinsic or mitochondrial pathway and the extrinsic or death receptor pathway. Both culminate in the activation of the effector caspases, such as caspase-3, resulting, for instance in DNA fragmentation and exposition of markers on the surface of the apoptotic cell, allowing its recognition and elimination by phagocytic cells. To ensure survival and proliferation, microorganisms can inhibit apoptosis of the host cell. The differential proteome of a tick cell line (BME26) in response to an experimental infection with Rickettsia rickettsii, causative agent of the severe Rocky Mountain spotted fever, showed that pro-apoptotic proteins are downregulated in the beginning of infection (6 h) and upregulated in a later time-point (48 h). We therefore evaluated the effects of infection on classic features of apoptotic cells: the spontaneous fragmentation of gDNA and the activity of caspase-3 and the exposition of phosphatidylserine in BME26 cells after induction with staurosporine, a classic activator of apoptosis. The spontaneous fragmentation of DNA was observed exclusively in non-infected cells. In addition, the activity of caspase-3 and the exposition of phosphatidylserine is lower in infected than in non-infected cells. Caspase-3 activity is also lower in infected IBU/ASE-16 cells, an embryonic tick cell line of one primary vector of R. rickettsii in Brazil, Amblyomma sculptum. Importantly, while the activation of caspase-3 exerted a detrimental effect on rickettsial proliferation in BME26 cells, the enzyme inhibition increased bacterial growth. Together, our results suggest that R. rickettsii controls the apoptosis in tick cells, which seems to be important to ensure the colonization of the vector cell. To the best of our knowledge, this is the first report on the modulation of the apoptosis in a tick cell line upon the infection with a species of the genus Rickettsia.

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Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis Through the Mitochondria‑Dependent Apoptosis in Human Gastric Cancer Cells

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