PPARβ/δ Agonist GW501516 Inhibits Tumorigenesis and Promotes Apoptosis of the Undifferentiated Nasopharyngeal Carcinoma C666-1 Cells by Regulating miR-206

Abstract

In previous investigations, we reported that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activation by GW501516 inhibits proliferation and promotes apoptosis in the undifferentiated C666-1 nasopharyngeal carcinoma (NPC) cells by modulating caspase-dependent apoptotic pathway. In the present study, the mechanism by which GW501516 induces apoptosis was explored from the perspective of microRNA (miRNA) expression. Among the assayed miRNAs that were involved in regulating the expression of antiapoptotic protein Bcl-2, miR-206 was increased significantly and specifically by GW501516 in C666-1 cells at both the in vitro level and at the in vivo xenograft samples. The induction on miR-206 expression caused by GW501516 was capable of being antagonized by the PPARβ/δ antagonist GSK3787 and AMPK antagonist dorsomorphin in C666-1 cells. GW501516’s suppression on the growth and apoptosis of C666-1 cells was found to be dependent on the presence of miR-206. miR-206 overexpression resulted in suppressed proliferation and colony formation ability, and further triggered increased apoptosis in C666-1 cells in a caspase-dependent manner. The expression of cleaved caspase 3 and caspase 9, and the ratio of Bax to Bcl-2 were elevated remarkably by miR-206. Consistent with the in vitro result, miR-206 was corroborated to suppress the ectopic NPC xenograft tumorigenesis that derived from the C666-1 cells in BALB/c nu/nu mice. Taken together, the current data demonstrated that miR-206 plays a critical role in the direct apoptosis-promoting effect induced by GW501516 in C666-1 cells. Furthermore, the emphasized tumor-suppressive role of miR-206 in the C666-1 cells indicates that it has the potential to provide a new therapeutic approach for the undifferentiated NPC.

PPAR Beta/Delta and the Hallmarks of Cancer

“…The authors proposed as underlying mechanisms the activation of adenosine monophosphate-activated protein kinase (AMPKα) and downregulation of integrin-linked kinase (ILK), as the AMPK inhibitor compound C was able to inhibit the reduction of ILK expression induced by GW501516 [118]. Employing the same cell line, the authors further implicated the microRNA miR-206 in the apoptosis promoting effects of PPARβ/δ activation, as they observed an induction of miR-206 upon GW501516 mediated PPARβ/δ activation, which could be antagonized by the PPARβ/δ antagonist GSK3787 or the AMPK antagonist dorsomorphin [119].…”

State-of-the-Art Clinical Results of Growth Hormone Secretagogues, SARM and Antagonists

“…The induction in mir-206 expression caused by gw501516 was able to be antagonized by the antagonist gsk3787 of pparβ/δ and by the dorsomorphine antagonist of ampk in cells c666-1. Suppression of gw501516 in the growth and apoptosis of c666-1 cells has been found to depend on the presence of mir-206 [58].…”

“…Current data has shown that mir-206 plays a critical role in the direct promotion effect of gw501516-induced apoptosis in c666-1 cells. Also, the emphasized tumor-suppressing role of mir-206 in c666-1 cells indicates that it has the potential to provide a new therapeutic approach [58].…”

Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer

“…Although cell proliferation in mouse LLC1 lung cancer cells was decreased upon activation of PPARβ/δ, LLC1 tumor growth in vivo was enhanced in mice with conditional vascular overexpression of PPARβ/δ, underlining the importance of crosstalk between the tumor stroma and cancer cells for tumor growth [ 11 ]. One study reported that PPARβ/δ activation promoted apoptosis and reduced the tumor growth of nasopharyngeal carcinoma cells [ 116 ]. PPARβ/δ was found to be highly expressed in liposarcoma compared to benign lipoma, and PPARβ/δ activation increased liposarcoma cell proliferation, which was mediated via the direct transcriptional repression of leptin by PPARβ/δ [ 117 ].…”