p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling

Abstract

Pancreatic cancer (PC) remains a highly lethal malignancy due to its unusual chemoresistance and high aggressiveness. A subpopulation of pancreatic tumor cells, known as cancer stem cells (CSCs), is considered responsible not only for tumor-maintenance, but also for its widespread metastasis and therapeutic failure. Here we investigated the role of p-21 activated kinase 4 (PAK4) in driving PC stemness properties. Our data demonstrate that triple-positive (CD24+/CD44+/EpCAM+) subpopulation of pancreatic CSCs exhibits greater level of PAK4 as compared to triple-negative (CD24−/CD44−/EpCAM−) cells. Moreover, PAK4 silencing in PC cells leads to diminished fraction of CD24, CD44, and EpCAM positive cells. Furthermore, we show that PAK4-silenced PC cells exhibit decreased sphere-forming ability and increased chemo-sensitivity to gemcitabine toxicity. PAK4 expression is also associated with enhanced levels of stemness-associated transcription factors (Oct4/Nanog/Sox2 and KLF4). Furthermore, our data show decreased nuclear accumulation and transcriptional activity of STAT3 in PAK4-silenced PC cells and restitution of its activity leads to restoration of stem cell phenotypes. Together, our findings deliver first experimental evidence for the involvement of PAK4 in PC stemness and support its clinical utility as a novel therapeutic target in PC.

Resistin potentiates chemoresistance and stemness of breast cancer cells: Implications for racially disparate therapeutic outcomes

“…Guha et al demonstrated a critical role of STAT3 in apoptosis resistance and development and maintenance of CSC characteristics in breast cancer cells [63]. In other cancers, such as pancreatic cancer, STAT3 has been shown to be important in maintaining stem cell phenotypes [32]. In addition to maintaining the stemness phenotypes, activation of STAT3 is also linked to the conversion of non-CSCs to CSCs [64].…”

“…After 15 days, the mammospheres were counted and photographed using phase contrast microscope, as described previously [32]. …”

Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

“…111) is a key factor in the maintenance of OCT4 , NANOG and SOX2 expression by binding to their enhancers during early mouse development 112 . As STAT3 also promotes proliferation, survival 113 and the acquisition of stem cell features in cancer 114 , one possibility is that chronic inflammation leads to unscheduled activation of epigenetic mediator genes in the cells of origin via STAT3 activation (FIG. 1; TABLE 1).…”

Downregulation of lncRNA-HOXA11-AS modulates proliferation and stemness in Glioma cells

“…The sphere-forming assays were performed [10]. Briefly, cells (1 × 10 3 /well) were cultured in ultra low attachment 6-well plates in 2 mL of stem cell culture media and the media was supplemented with 2% B27, 20 ng/mL EGF and 20 ng/mL FGF-b on every other day.…”