ST6Gal-I modulates docetaxel sensitivity in human hepatocarcinoma cells via the p38 MAPK/caspase pathway

Abstract

The β-galactoside α2-6-sialyltransferase 1 (ST6Gal-I) is the principal sialyltransferase responsible for the addition of α2-6-sialic acid to the termini N-glycans on cell surface. Although ST6Gal-I in cancer cell resistance to chemotherapeutics agents has been previously reported, the role of ST6Gal-I in clinical drug resistance of hepatocellular carcinoma (HCC) is not fully understood. In this study, we found that knockdown of ST6Gal-I increased the sensitivity of hepatocarcinoma MHCC97-H cells to docetaxel treatment by instigating the process of apoptosis. Silencing ST6Gal-I expression decreased the survival rate of MHCC97-H cells after docetaxel treatment. Importantly, ST6Gal-I silencing resulted in an increasing of phospho-p38, Bax, Bad, cytochrome c and the cleaved caspase-9, 3 and PARP, while a decreasing of the anti-apoptotic protein Bcl-2. In addition, we found that p38 MAPK and caspase-3 inhibitors can reduce the enhanced apoptosis levels of MHCC97-H cells resulted by either ST6Gal-I silencing or docetaxel treatment. Conversely, exogenous expression of ST6Gal-I in hepatocarcinoma Huh7 cells inhibited apoptotic cell death and prevented docetaxel-induced apoptosis by inhibiting p38 MAPK mediated mitochondrial-dependent pathway. Taken together, these results indicate that ST6Gal-I might play a positive role in mediating the survival of human hepatocarcinoma cells and could be a potential target for gene and antitumor drugs therapy.

Plectin protects podocytes from adriamycin‐induced apoptosis and F‐actin cytoskeletal disruption through the integrin α6β4/FAK/p38 MAPK pathway

“…P38 likely mediates podocyte injury by triggering apoptosis and F‐actin reorganization. p38 activation has been shown in many previous studies to be strongly correlated with increases in the expression levels of the apoptosis‐related proteins Bax and cleaved caspase‐3 . In this study, p38 inhibition reduced siPlectin‐induced podocyte apoptosis and decreased Bax and cleaved caspase‐3 expression, findings that are consistent with those of prior studies.…”

“…p38 activation has been shown in many previous studies to be strongly correlated with increases in the expression levels of the apoptosis-related proteins Bax and cleaved caspase-3. 54,55 In this study, p38 inhibition reduced siPlectin-induced podocyte apoptosis and decreased Bax and cleaved caspase-3 expression, findings that are consistent with those of prior studies. Previous studies have also shown that p38 activation inhibits actin polymerization and decreases F-actin levels to maintain a dynamic and balanced F-actin cytoskeleton and normal podocyte foot process structures.…”

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

“…ST6Gal-I regulates tumor cell phenotype by modulating the sialylation, and therefore function, of key receptors that drive malignant cell behaviors [11][12][13][14][15][16][17]. We and others have shown that ST6Gal-I activity confers all of the hallmark features of a CSC including increased expression of canonical CSC markers [18], invasive potential [16,19], tumor-initiating potential [9,20], and resistance to hypoxia, chemotherapeutics, and radiation [14,[20][21][22][23][24][25].…”

The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling

“…Recent studies suggest that a central cornerstone of ST6Gal-I's pro-tumorigenic function is its role in conferring a CSC phenotype (18). ST6Gal-I expression correlates with established CSC markers such ALDH1 and CD133 (19), and ST6Gal-I activity imparts hallmark CSC characteristics, including tumor spheroid growth, cell invasiveness, tumor-initiating potential, and resistance to cytotoxic stimuli, including chemotherapeutic drugs (18,(23)(24)(25)(26)(27)(28)(29)(30)(31). ST6Gal-I also promotes epithelial-to-mesenchymal transition (32).…”