OBJECTIVE: To investigate the effects of Lathyrol on the expression of androgen receptor (AR) and sphingosine kinase 2 (SPHK2) in renal cell carcinoma (RCC) mice and to further explore the mechanism by which Lathyrol inhibits the invasion and incidence of epithelial-mesenchymal transition (EMT).
METHODS: An RCC xenograft mouse model was constructed, and the mice were randomly divided into a model group, an experiment group and a negative control group. The experiment group was intragastrically gavaged with Lathyrol solution (20 mg/kg), the model group was intragastrically gavaged with 0.9% NaCl (same volume as that used in the experiment group), and the negative control group was injected intraperitoneally with 2 mg/kg cisplatin aqueous solution. Changes in the body weight and tumor volume of the mice were recorded. Western blot (WB) was used to assess the protein expression levels of AR, p-AR, CYP17A1, PARP1, E-cadherin, N-cadherin, vimentin, α-SMA, β-catenin, and ZO-1. Protein expression levels of SPHK2, metal matrix protease 2 (MMP2), MMP9 and urokinase-type plasminogen activator (uPA) in tumor tissues were assessed by immunohistochemistry (IHC). AR expression in tumor tissues was assessed after immunofluorescence (IF) staining.
RESULTS: After 14 days of drug administration, compared with that in the model group, the tumor volumes in the negative control and experiment groups were lower; the difference in tumor volume among the model, control and experiment groups was statistically significant (P < 0.05). The differences in body weight among the three groups were not statistically significant (P > 0.05). In the model group, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively increased, the protein expression levels of E-cadherin and ZO-1 were relatively reduced (P < 0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin, and α-SMA were relatively increased (P < 0.05). In the negative control and experiment groups, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively decreased (P < 0.05), the protein expression levels of E-cadherin and ZO-1 were relatively increased (P < 0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA were relatively decreased (P < 0.05).
CONCLUSIONS: Lathyrol and cisplatin inhibit the proliferation of RCC xenografts, reduce the protein expression levels of AR, CYP17A1, SPHK2, PARP1, E-cadherin, and ZO-1 in tumor tissues (P < 0.05), and promote the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA (P < 0.05). Therefore, Lathyrol reduces RCC invasion and EMT by affecting the expression of AR and SPHK2 in RCC mice.

Lathyrol is a natural product isolated from the traditional Chinese medicine Semen Euphorbiae with unknown anti-tumor effects. We found that lathyrol had significant inhibitory effect on lung cancer cells by inducing apoptosis and inhibiting proliferation. Subsequently, we demonstrated for the first time that endoplasmic reticulum (ER) stress is a key anti-tumor mechanism of lathyrol. Furthermore, we found that lathyrol can induce ER stress in lung cancer cells by upregulating the protein expression levels of GRP78, PERK, p-eIF2α, CHOP, and ATF4, and the inhibitory effect of lathyrol on lung cancer cells was significantly reversed when cells were pretreated with ER stress inhibitor. In addition, we found that inhibition of SERCA2 resulted in depletion of the ER Ca2+ pool followed by a sustained increase in cytoplasmic Ca2+ levels, eventually leading to ER stress induced tumor cell apoptosis and proliferation inhibition. Lathyrol targeted SERCA2 to cause a significant upregulation of Ca2+ levels, and the inhibitory effect of lathyrol on lung cancer cells was significantly reversed after pretreatment with SERCA2 agonist. Taken together, our data suggest that lathyrol exerts its anti-tumor effect primarily by targeting SERCA2. Our findings highlight the potential for lathyrol as a new candidate drug for the treatment of lung cancer.