Abstract
Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) had been linked to inhibition on the proliferation and apoptosis in a few cancer cell lines. However, limited data exists regarding the role of PPARβ/δ in nasopharyngeal carcinoma (NPC). This study was undertaken to determine the effect of PPARβ/δ on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the human NPC cell lines. Gene and protein expression of PPARβ/δ were reduced specifically in the poor- and un-differentiated NPC cell lines as compared with the control NP-69 cells. Ligand activation of PPARβ/δ by GW501516, a specific PPARβ/δ selective agonist, inhibited cell proliferation and colony formation strikingly, and induced a G2/M phase arrest in the EBV positive undifferentiated NPC C666-1 cells relative to the control cells. Moreover, GW501516 induced C666-1 cell apoptosis in a caspase and BAX dependent manner. In accordance with the in vitro result, GW501516 significantly suppressed the ectopic NPC xenograft tumorigenicity that derived from the C666-1 NPC cells in BALB/c nu/nu mice. This effect is greatly associated with its inhibition on the gene and protein expression of integrin-linked kinase (ILK) through activation of the AMPKα-dependent signaling pathways. Collectively, we showed that PPARβ/δ expression is in reverse correlation with the degree of differentiation in the NPC cell lines, and revealed the anti-tumorigenic effects of GW501516 in NPC cells by activation of AMPKα. This study suggested that PPARβ/δ targeting molecules may be useful for the poor-, and particularly un-differentiated NPC chemoprevention.
Highlights
Nasopharyngeal carcinoma (NPC), a malignant carcinoma arising from the epithelial lining of the nasopharynx, is constantly associated with the Epstein Barr Virus (EBV), only the EBV genome instead of viral particles was observed in the nucleus of the malignant nasopharyngeal carcinoma (NPC) cells (Shannon-Lowe et al, 2009)
We found peroxisome proliferator-activated receptor β/δ (PPARβ/δ) expression is in reverse correlation with the degree of differentiation in the NPC cell lines, the most striking reduction was observed in the EBV positive undifferentiated NPC C666-1 cells, where GW501516 treatment could inhibit the growth of NPC cells at both in vitro and in vivo level, through impairing cell cycle progression and promoting apoptosis by activation of the
While no decrease was observed on expression of PPARβ/δ mRNA and protein in the two well differentiated EBV-negative (HK1, CNE1) NPC cell lines, and even a slight increase on PPARβ/δ mRNA expression was found in the HK1 cells (p < 0.05)
Summary
Nasopharyngeal carcinoma (NPC), a malignant carcinoma arising from the epithelial lining of the nasopharynx, is constantly associated with the Epstein Barr Virus (EBV), only the EBV genome instead of viral particles was observed in the nucleus of the malignant NPC cells (Shannon-Lowe et al, 2009). NPC is relatively radiosensitive and chemosensitive among head and neck tumors, there are about 19–69% of patients will still experience the recurrence of NPC after initial treatment (Yang et al, 1996; Li et al, 2010; Suárez et al, 2010; Kong and Lu, 2016). Diversified therapeutic agents for systemic treatments or as adjuvant chemotherapies to amplify currently available treatment protocols are desperately needed for improving the management of NPC (Kong and Lu, 2016). Novel approaches targeting of pivotal gene products whose function directly drives NPC will facilitate this process. Molecular targeted therapy is still unavailable in the therapy of NPC, and substitute treatment options remain rather poor (Zhang et al, 2013; Tan et al, 2016)
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