High COX-2 expression contributes to a poor prognosis through the inhibition of chemotherapy-induced senescence in nasopharyngeal carcinoma

Abstract

Resistance to radiotherapy and chemotherapy currently represents one of the major reasons for therapeutic failure in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying resistance to chemotherapy in NPC remain unclear. In this study, cell counting assay, cell cycle assay and senescence associated β-galactosidase activity were performed to evaluate cell growth, proliferation and senescence, respectively. We found that the aberrant expression of cyclooxygenase-2 (COX-2) was associated with a poor outcome and recurrance in patients with NPC. In NPC cells, COX-2 overexpression increased cell proliferation, inhibited cellular senescence and resulted in chemoresistance, while the knockdown of COX-2 reduced cell proliferation, promoted cellular senescence and overcame chemoresistance. Furthermore, fibroblasts from COX-2 knockout mice exhibited cellular senescence, particularly when treated with chemotherapeutic agents. Mechanistically, COX-2 interacted with p53 protein and inhibited cellular senescence, which resulted in chemotherapeutic resistance. On the whole, these findings indicate that COX-2 may play a critical role in chemotherapeutic resistance in NPC via the inhibition of chemotherapy-induced senescence via the inactivation of p53. This study provides experimental evidence for the preclinical value of increasing chemotherapy-induced senescence by targeting COX-2 as an effective antitumor treatment in patients with recurrent NPC.

High COX‐2 expression in cancer‐associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma

“…Our studies and other groups demonstrated that high expression of COX-2 contributes to tumor cell proliferation, metastasis, and drug resistance through regulating several oncogenes or cellcycle-related molecules such as p53, β-catenin, Snail1, etc, in NPC and other cancers. 30,41,42 However, in our study, we found TNF-α, another new molecular positively correlated with COX-2 by RNA-Seq. Bourouba 43 showed that TNF-α promotes tumor growth via a NOS2-dependent mechanism in NPC.…”

“…40 Our previous studies showed that a high expression of COX-2 is associated with the recurrence and a poor prognosis of patients with NPC, and COX-2 may play a critical role in chemotherapeutic resistance in NPC via the inhibition of chemotherapy-induced senescence via the inactivation of p53. 30 However, these studies revealed that the COX-2 expression in NPC cells, to the date, there is no report referred to the COX-2 expression of TME in NPC. Several studies revealed that COX-2 promotes tumor metastasis, for example, Zelei reported that COX-2 is highly expressed in NPC cells, which promote the expansion of myeloid-derived suppressor cells with a suppressive function on T cells through inducing the cytokine secretion including IL-6 and GM-CSF.…”

“…Of note, COX‐2 is highly expressed in numerous types of human cancer, such as breast, ovarian, colorectal cancer, and NPC . Our previous studies reported that COX‐2 serves as a marker of poor prognosis in NPC, and COX‐2 expression induces proliferation and chemoresistance of NPC cells . However, stromal expression of COX‐2 has not been specifically evaluated in NPC to date.…”

“…[26][27][28][29] Our previous studies reported that COX-2 serves as a marker of poor prognosis in NPC, and COX-2 expression induces proliferation and chemoresistance of NPC cells. 30 However, stromal expression of COX-2 has not been specifically evaluated in NPC to date.…”

The p53-p21 axis plays a central role in lymphatic homeostasis and disease

“…To confirm the contribution of p53 overexpression to lymphedema, we used a pharmacological approach by testing a known reversible p53 negative modulator, Pifithrin-α (PFT) 44,45 . For this, we set up time mating of Rpl27a low/+ mice with Mdm2 +/or Mdm4 +/mice.…”