Mahanine drives pancreatic adenocarcinoma cells into endoplasmic reticular stress-mediated apoptosis through modulating sialylation process and Ca2+-signaling

被引：11

作者：

Bhattacharya, Sayantani Sarkar ^{[1
]}

Mandal, Chandan ^{[1
]}

Albiez, Reinhard Schwartz ^{[2
]}

Samanta, Suman Kumar ^{[1
]}

Mandal, Chitra ^{[1
]}

机构：

[1] Council Sci & Ind Res Indian Inst Chem Biol, Canc Biol & Inflammatory Disorder Div, Kolkata 700032, India

[2] German Canc Res Ctr Heidelberg, Antigen Presentat & T NK Cell Activat, Clin Cooperat Unit Appl Tumor Immun, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; UNFOLDED PROTEIN RESPONSE; SIALATE-O-ACETYLTRANSFERASE; SIALIC-ACID RESIDUES; DIFFERENTIAL EXPRESSION; ER STRESS; PATHWAY; CANCER; ACTIVATION; INHIBITION;

D O I：

10.1038/s41598-018-22143-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Endoplasmic reticulum (ER) stress results from protein unfolding/misfolding during cellular maturation, which requires a coordinated action of several chaperones and enzymes and Ca2+ signalling. ER-stress possibly has a positive effect on survival of pancreatic cancer cell. Therefore, detailed insights into this complex signaling network are urgently needed. Here, we systematically analyzed the impact of ER stress-mediated unfolded protein response (UPR) and Ca2+-signaling cross-talk for the survival of pancreatic adenocarcinoma (PDAC) cells. We observed enhanced ER activity and initiation of UPR signaling induced by a carbazole alkaloid (mahanine). This event triggers a time-dependent increase of intracellular Ca2+ leakage from ER and subsequently Ca2+ signaling induced by enhanced reactive oxygen species (ROS) produced by this pro-oxidant agent. In addition, we observed an altered glycosylation, in particular with regard to reduced linkage-specific sialic acids possibly due to decreased sialyltransferase activity. Changes in sialylation entailed enhanced expression of the ganglioside GD3 in the treated cells. GD3, an inducer of apoptosis, inhibited pancreatic xenograft tumor. Taken together, our study describes a molecular scenario how PDAC cells are driven into apoptosis by mahanine by UPR-driven ER stress-associated and ROS-mediated calcium signaling and possibly defective sialylation.

引用

页数：12