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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Saucerneol attenuates nasopharyngeal carcinoma cells proliferation and metastasis through selectively targeting Grp94
Yanfang Cheng1, Qian Wang1, Zhikang Zhang1
1Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
Background:
Nasopharyngeal carcinoma (NPC) is highly prevalent in southern China. The remote metastasis of advanced NPC requires chemotherapeutic treatments to reduce the mortality. Our previous work revealed that saucerneol (SN) showed cytotoxicity against several nasopharyngeal carcinoma (NPC) cells. This work aims to investigate the effect of SN in NPC growth and exploring the mechanism of action.
Study Design:
Applying in vivo study, in vitro study and in silico study to indicate the mechanism of SN in inhibiting NPC growth.
Methods:
Saucerneol (SN) toxicity was measured with MTT assay. NPC proliferation was measured with EdU and colony formation assays, cell cycle was detected with flow cytometry. NPC migration and invasion were measured with scratch assay and matrigel transwell method. Further, human NPC xenograft tumor models were established in nude mice to evaluate the therapeutic efficacy of SN in vivo. Toxicological analysis was performed on H&E staining and IHC. Quantitative real-time PCR and Western blot analyses were used to evaluate the expression levels of key molecules in PI3K/AKT/mTOR, MAPK, NF-κB, and HIF-1α signal pathways. Target predicting was conducted using computational method, and target identification was carried out by ATPase assay and TSA.
Results:
SN, a potent NPC inhibitor that was previously isolated from Saururus chinensis in our lab, is proven to inhibit the proliferation and metastasis of HONE1 cell lines and inhibit the growth of human NPC xenografts in nude mice. Moreover, we further articulate the molecular mechanism of action for SN and, reveal that SN promotes the expression of cell cycle-dependent kinase inhibitory protein p21 Waf1/Cip1 through targeting Grp94 and then inhibiting PI3K/AKT signaling pathway as well as up-regulating p53 to disrupt the progression of HONE1 cells.
Conclusion:
SN significantly inhibits NPC cells proliferation and metastasis in vitro and in vivo via selectively inhibit Grp94 and then blocking PI3K/AKT/mTOR/HIF-1α signaling pathway. This study firstly provides a novel selective Grp94 inhibitor as a NPC candidate.
Insights
Saucerneol (SN) inhibits nasopharyngeal carcinoma (NPC) growth and metastasis by targeting Grp94. This natural compound offers a potential new therapeutic strategy for advanced NPC, reducing mortality.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Nasopharyngeal carcinoma (NPC) is prevalent in Southern China, with advanced stages requiring chemotherapy.
- Remote metastasis of NPC significantly increases mortality rates.
- Saucerneol (SN), isolated from Saururus chinensis, demonstrated prior cytotoxicity against NPC cells.
Purpose of the Study:
- To investigate the anti-cancer effects of Saucerneol (SN) on nasopharyngeal carcinoma (NPC) growth.
- To elucidate the molecular mechanisms underlying SN's action in NPC.
Main Methods:
- In vitro assays (MTT, EdU, colony formation, cell cycle, scratch, transwell) and in vivo xenograft models were employed.
- Molecular mechanisms were explored using Western blot, qRT-PCR, and computational target prediction.
- Key signaling pathways including PI3K/AKT/mTOR, MAPK, NF-κB, and HIF-1α were analyzed.
Main Results:
- SN inhibited NPC cell proliferation and metastasis in vitro and suppressed human NPC xenograft growth in vivo.
- SN upregulates p21 Waf1/Cip1 and p53, leading to cell cycle disruption.
- SN targets Grp94, inhibiting the PI3K/AKT signaling pathway.
Conclusions:
- SN exhibits significant anti-proliferative and anti-metastatic effects on NPC cells, both in vitro and in vivo.
- The mechanism involves selective inhibition of Grp94, consequently blocking the PI3K/AKT/mTOR/HIF-1α pathway.
- SN represents a novel, selective Grp94 inhibitor with potential as a therapeutic candidate for NPC.
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