Evidence that cervical cancer cells cultured as tumorspheres maintain high CD73 expression and increase their protumor characteristics through TGF-ß production.

Recently, a link between the biological activity of CD73 and tumorigenicity in solid tumors has been proposed. We previously reported that the generation of adenosine (Ado) by the activity of CD73 in cervical cancer (CC) cells induces transforming growth factor-beta 1 (TGF-ß1) production to maintain CD73 expression. In the present study, we analyzed the participation of TGF-ß1 in CD73 expression and the development of protumoral characteristics in CaSki CC cells cultured as tumorspheres (CaSki-T) and in monolayers (CaSki-M). Compared with those in CaSki-M cells, CD73 expression and Ado generation ability were significantly increased in CaSki-T cells. CaSki-T cells exhibited enrichment in the CSC-like phenotype due to increases in the expression levels of stem cell markers (CD49f, CK17, and P63; OCT4 and SOX2), greater sphere formation efficiency (SFE), and an increase in the percentage of side population (SP) cells. Interestingly, compared with CaSki-M cells, CaSki-T cells produced a greater amount of TGF-ß1 and presented a marked protumor phenotype characterized by a significant decrease in the expression of major histocompatibility complex class-I (MHC-I) molecules, an increase in the expression of multidrug resistance protein-I (MRP-I) and vimentin, and an increase in the protein expression levels of Snail-1 and Twist, which was strongly reversed with TGF-ß1 inhibition. These results suggest that the presence of TGF-ß1-CD73-Ado feedback loop can promote protumoral characteristics in the CC tumor microenvironment.

Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells.

(25R)-spirost-5-en-3ß-ol, also known as diosgenin (DSG), exerts antiproliferative activity on diverse cell lines, induces apoptosis, and acts as a chemopreventative agent. However, the relationship between DSG glycosides and apoptotic, necrotic, and antiproliferative activity remains unclear. It is in this regard that we report the antiproliferative, necrotic, and apoptotic activities of DSG and its glycoside derivatives: (25R)-spirost-5-en-3ß-yl O-ß-D-glucopyranoside (3GD), (25R)-spirost-5-en-3ß-yl O-α-L-rhamnopyranosyl-(1 â†’ 4)-ß-D-glucopyranoside (3GRD); and (25R)-spirost-5-en-3ß-yl O-α-L-rhamnopyranosyl-(1 â†’ 2)-O-[α-L-rhamnopyranosyl-(1 â†’ 4)]-ß-D-glucopyranoside), also known as dioscin (DSC), in in vitro assays of cervical HeLa and CaSki cancer cells. The results demonstrated that DSG glycosidic derivatives preserved their antiproliferative activity. However, in both cancer cell lines, 3GD and 3GRD were less potent than DSG, while DSC was more potent than DSG. With respect to necrotic activity, all tested compounds showed no or low activity on the two cervical cancer cell lines. Regarding apoptosis, the results showed that DSG glycosides were better apoptosis-inducers than DSG, suggesting that glucose and rhamnose residues play a central role in enhancing the apoptotic activity of DSG. Finally, DSG and its glycosidic derivatives were shown to affect the proliferative potential of lymphocytes (non-tumour cells) to a lesser extent than cancer cells, suggesting that these compounds have selective action. In conclusion, the results indicate that DSG and its glycosidic derivatives are promising anticancer compounds since they are compounds with low necrotic activity and selective action.