Abstract
Senescence is an irreversible state of cell cycle arrest that can be triggered by multiple stimuli, such as oxygen reactive species and DNA damage. Growing evidence has proven that senescence is a tumor-suppressive approach in cancer treatment. Therefore, developing novel agents that modulate senescence may be an alternative strategy against cancer. In our study, we investigated the inhibitory effect of gypenoside L (Gyp-L), a saponin isolated from Gynostemma pentaphyllum, on cancer cell growth. We found that Gyp-L increased the SA-β-galactosidase activity, promoted the production of senescence-associated secretory cytokines, and inhibited cell proliferation of human liver and esophageal cancer cells. Moreover, Gyp-L caused cell cycle arrest at S phase, and activated senescence-related cell cycle inhibitor proteins (p21 and p27) and their upstream regulators. In addition, Gyp-L activated p38 and ERK MAPK pathways and NF-κB pathway to induce senescence. Consistently, adding chemical inhibitors efficiently counteracted the Gyp-L-mediated senescence, growth inhibition, and cell cycle arrest in cancer cells. Furthermore, treatment with Gyp-L, enhanced the cytotoxicity of clinic therapeutic drugs, including 5-fluorouracil and cisplatin, on cancer cells. Overall, these results indicate that Gyp-L inhibits proliferation of cancer cells by inducing senescence and renders cancer cells more sensitive to chemotherapy.
Highlights
The current therapeutic strategies against cancer include chemotherapy, radiotherapy, surgery or combinations of them
We detected the senescence-associated expression of senescence-associated secretory phenotype (SASP), such as IL-1α, IL-6, TIMP-1, CXCL-1 and CXCL-2, by Quantitative Real-Time PCR (qRT-PCR) (Figure 1C)
The mRNA expression levels of all cytokines were increased by gypenoside L (Gyp-L). These results indicate that Gyp-L induces senescence in human cancer cells
Summary
The current therapeutic strategies against cancer include chemotherapy, radiotherapy, surgery or combinations of them. Treatment of cancer by DNA-damaging chemotherapy is based on the principle that the genomic instability of cancers has a greater propensity to accumulate DNA damage. Genotoxic drugs, such as alkylating agents, mainly cause DNA fracture and interfere with DNA replication to inhibit tumor cell division, which usually trigger DNA damage repair response (DDR) [1,2]. Cancer cells have evolved to usurp various strategies to promote cell cycle progression, to evade cell death and to develop chemoresistance [3,4]. A growing amount of evidence has proved that senescence is a critical tumor-suppressive approach in cancer treatment and prevention [5,6,7].
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