Cancer, a major cause of mortalities across the globe overexpresses sialic acids (Sia), a 9 carbon sugar residue on the surfaces of cells. This has been identified as a hallmark of cancer and its progression. Sialic acid can be highly functionalized, but we became interested in acetylated Sias. This functional group is modulated by Sialate O- acetylesterase (encoded by the gene SIAE) and Sialate O-acetyltransferase (encoded by CASD1), enzymes that play a crucial role in functionalizing sialic acid. CASD1 and SIAE catalyze the addition and removal of acetyl groups to sialic acids respectively. Our findings show that targeting SIAE and CASD1 in chemotherapy renders it more susceptible to drugs that target and inhibit tumor cell proliferation via EGFR signaling. Chemically synthesized novel hybrid analogs (MMA 294, 320 and 321) and Sorafenib exhibited an apoptotic mode of cytotoxicity on colon and lung cancer cells when analyzed with the Annexin V/7-AAD assay. The effect of these drugs on the cell cycle of HCT116 and A549 cells was also assessed using DNA staining with propidium iodide. MMA 294 and sorafenib elicited a G0/G1 cell cycle arrest in A549 WT and ΔCASD1 cells but a G2/M in A549 SIAE. MMA 321 also showed a switch in cell cycle arrest from G0/G1 in WT and HCT116 ΔCASD1 to a G2/M in HCT116 SIAE cells. Further screening of activated EGFR by immunofluorescence revealed an overexpression of pEGFR in the CASD1 and SIAE knockout cells suggesting an increased activation of this growth receptor rendering the knockout cells highly proliferative but extremely sensitive to the novel hybrid analogs of estrone origin.

Dysregulation of CASD1 and SIAE increases susceptibility of colon and lung cancers to targeted therapy by recepotor tyrosine kinase inhibitors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.