Tunicamycin enhances the suppressive effects of cisplatin on lung cancer growth through PTX3 glycosylation via AKT/NF-κB signaling pathway

Abstract

Long pentraxin-3 (PTX3) is an inflammatory molecule related to cancer proliferation, invasion, and metastasis. Many studies have highlighted the significance of glycosylated molecules in immune modulation, inflammation and cancer progression. Moreover, aberrant glycosylation of cancer cells is linked to chemoresistance. This study aimed to develop effective therapeutic strategies for deglycosylation of PTX3 (dePTX3) in order to enhance chemosensitivity to cisplatin (Cis) in lung cancer treatment. The A549 and SPCA1 cells were used to determine the role of PTX3 glycosylation in lung cancer growth. Our results revealed that PTX3 was higher in both human lung cancer tissues and serum in comparison with control. Furthermore, we found that deglycosylated PTX3 (dePTX3) by tunicamycin (TM), which is N-glycan precursor biosynthesis blocker, and PNGase F significantly reduced the survival and migration of lung cancer cells. To further confirm this, we also generated glycosylation-site mutant of PTX3 (mPTX3) to characterize the loss of glyco-function. dePTX3 and TM enhanced the suppressive effects of Cis on lung cancer cell growth, migration and invasion compared to individual treatment. Treatment with a combination of TM and Cis significantly inactivated AKT/NF-κB signaling pathway and induced apoptosis. In conclusion, these findings suggest that PTX3 is an important mediator of lung cancer progression, and dePTX3 by TM enhances the anticancer effects of Cis. The deglycosylation in chemotherapy may represent a potential novel therapeutic strategy against lung cancer.

K284-6111 Alleviates Memory Impairment and Neuroinflammation in Tg2576 Mice by Inhibition of Chitinase-3-like 1 Regulating ERK Dependent PTX3 Pathway

“…Qi et al reported that silencing of PTX3 mitigates the LPS-induced in ammatory response in BV-2 cells and mice, which occurs by down-regulating the TLR4/NF-κB signaling pathway [65]. Ahmmed et al showed when they caused the deglycosylation of PTX3 and changed its function, the AKT/NF-κB signaling pathway was inactivated [66]. These data indicated that PTX3 pathway could play a signi cant role in K284-6111 inhibiting effect on CHI3L1-mediating M1-speci c neuroin ammation associated with AD development.…”

Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia

“…In lung cancer cells, deglycosylation of human pentraxin-3 (PTX3) protein by TM enhanced the sensitivity to therapy via AKT/NF-κB signaling pathway. TM inhibits glycosylation of plasma membrane receptors, resulting in impaired transport of these receptors to the cell surface [76,77].…”

“…TM arrested underglycosylated FLT3-ITD in an endoplasmic reticulum-bound form to activated STAT5 [78]. But mere retention of FLT3 in the endoplasmic reticulum is not sufficient to activate signaling and mutation of FLT3 is necessary for initiation of downstream STAT5 signaling from the endoplasmic reticulum [77]. In FLT3-ITD mutant cells, TM has been confirmed to arrest underglycosylated FLT3-ITD in the endoplasmic reticulum and to promote STAT5 activation [55,78].…”

Silencing of PTX3 alleviates LPS-induced inflammatory pain by regulating TLR4/NF-κB signaling pathway in mice

“…It activates effectors under inflammatory conditions and is an important component of innate immunity [8]. PTX3 expression is regulated by various signaling pathways, such as NF-κB, JNK and PI3K/Akt signaling pathways [9]. PTX3 was originally identified as the inducible genes of IL-1 and TNF-α, which are widely involved in the regulation of inflammatory diseases, such as pneumonia, cystitis and cancer-related inflammation [10].…”