Dysregulation of the PI3K/Akt signaling pathway affects cell cycle and apoptosis of side population cells in nasopharyngeal carcinoma

Abstract

Abstract.Increasing evidence has suggested that certain types of cancer possess their own stem-like cells, and that one subset of these cells, termed the side population (SP), may have an important role in tumorigenesis and cancer therapy. However, the molecular mechanisms underlying the modulation of SP cells in nasopharyngeal carcinoma (NPC) have remained elusive. In the present study, it was hypothesized that dysregulation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signaling pathway may influence SP and non-SP (NSP) phenotype. SP cells from the HK-1 NPC cell line were identified, and cancer stem cell markers were found to be highly expressed in SP cells compared with that of NSP cells. Freshly sorted SP cells demonstrated a significant increase in the proportion of cells in G0/G1 phase, while the majority of NSP cells were in the proliferative phase. Following 48 h of culture subsequent to cell sorting, the differences in cell cycle distribution between the SP and NSP cells converged. In addition, the apoptotic ratio of NSP cells was higher than that of SP cells at 24 h following sorting, but had no significant differences 48 h following sorting. To elucidate the potential mechanism mediating the cell cycle and apoptosis in SP cells, the expression levels of key molecules in the PI3K/Akt signaling pathway were evaluated. PI3K and Akt were upregulated, while 14-3-3σ protein was downregulated in SP cells when freshly sorted (0 h). However, there was no significant difference in the expression of these molecules between SP and NSP cells following 48 h of culture. These results suggested that dysregulation of the PI3K/Akt signaling pathway may be associated with the cell cycle and apoptosis of SP cells in NPC. However, further investigation is required to elucidate the detailed mechanisms underlying these effects. IntroductionIncreasing evidence has suggested that specific types of cancer may contain their own stem-like cells, known as cancer stem cells (CSCs), which have key roles in the initiation, maintenance and recurrence of tumors (1-3). In particular, attention has been paid to a subset of CSCs, termed the side population (SP), which was identified by flow cytometry. These SP cells are able to exclude the DNA binding dye, Hoechst 33342, and are highly enriched for stem cells in numerous types of tissue (4-6). SP cells have been isolated from multiple solid tumors, and studies have suggested that they may have significant roles in tumorigenesis and cancer therapy. A SP of cells in nasopharyngeal carcinoma (NPC) were found to exhibit characteristics of stem-like cancer cells (7-12). However, the molecular mechanisms underlying the modulation of these stem-like cell populations in NPC have remained elusive. Cellular proliferation is a critical process underlying the growth, development and regeneration of eukaryotic organisms, and appropriate control of the cell cycle is required for the proliferation of normal cells (13,14). Deregulation of the cell cycle is responsible for the aberrant...

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

“…8,9) Additionally, AKT inactivates Bad and caspase-9, two pro-apoptotic proteins, 13) whereas inhibition of AKT signaling induces cell death by reducing the expression of Bcl-2 and enhancing the expression of Bax or Bad. 14) Our results show that QI treatment decreased the TP-induced activation of AKT and GSK3β. We also found that these QI-induced decreases in p-AKT and p-GSK3β levels paralleled reduced cyclin D1 expression and a decrease in the Bcl-2/Bax ratio.…”

“…8,9,13,14) Quisqualis indica (QI), commonly known as Chinese honeysuckle or Rangoon creeper, is a vine of the Combretaceae family that grows in tropical Asian countries, such as China, the Philippines, Bangladesh, Myanmar, India, and Malaysia.…”

“…6) Over-stimulation of the AKT pathway increases the activity of B-cell lymphoma 2 (Bcl-2) and cyclin D1, leading to increased proliferation and decreased apoptosis of cells, and transformation to the malignant state. 8,9,13,14) Quisqualis indica (QI), commonly known as Chinese honeysuckle or Rangoon creeper, is a vine of the Combretaceae family that grows in tropical Asian countries, such as China, the Philippines, Bangladesh, Myanmar, India, and Malaysia. 15) Different parts of this plant have compounds such as quisqualic acid, the alkaloid trigonelline, the flavonoid rutin, the amino acids L-proline and L-asparagine, and two forms of the enzyme cysteine synthase (isoenzymes A and B).…”

Cyclic Compressive Stress Regulates Apoptosis in Rat Osteoblasts: Involvement of PI3K/Akt and JNK MAPK Signaling Pathways

“…It has been reported that inhibition of the PI3K/Akt pathway can induce cell death[30]. Phosphorylated Akt functions as a survival signal partially by inactivating two pro-apoptotic proteins, Bad and caspase-9[31].…”

Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer

“…The PI3K (phosphoinositide 3-kinase)/Akt signaling pathway is a major driving force in a variety of cellular functions. Dysregulation of this pathway has been implicated in many human diseases including cancer (9)(10)(11)(12). Therapy resistance is critical to tumor maintenance and severely limits Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer cancer patient survival.…”