TNFAIP8 promotes cisplatin resistance in cervical carcinoma cells by inhibiting cellular apoptosis

Abstract

Cervical cancer is the second most prevalent malignant tumor in women worldwide. Failure of successful treatment is most prevalent in patients with the metastatic disease and the chemotherapy refractory disease. Tumor necrosis factor α-induced protein 8 (TNFAIP8) serves as an anti-apoptotic and pro-oncogenic protein, and is associated with cancer progression and poor prognosis in a number of different cancer types. However, the physiological and pathophysiological roles of TNFAIP8 in cervical carcinogenesis and development remain poorly understood. In the present study, it was demonstrated that TNFAIP8 protein expression levels were significantly increased in cervical cancer tissues compared with the non-tumor adjacent tissues using immunohistochemistry. Additionally, it was demonstrated that TNFAIP8 overexpression is associated with cisplatin resistance. Furthermore, depletion of TNFAIP8 impaired HeLa cell proliferation and viability in vitro, improved cisplatin sensitivity, and promoted cisplatin-induced cellular apoptosis and death. Subsequent mechanistic analysis demonstrated that TNFAIP8 silencing promoted caspase-8/-3 activation and p38 phosphorylation in HeLa cells treated with cisplatin, whereas apoptosis regulator B-cell lymphoma-2 expression was inhibited with TNFAIP8-silenced HeLa cells following treatment with cisplatin. These data suggested that TNFAIP8 serves as an anti-apoptotic protein against cisplatin-induced cell death, which eventually leads to chemotherapeutic drug-treatment failure. Therefore, the present data suggested that TNFAIP8 may be a promising therapeutic target for the treatment of cervical cancer.Abbreviations: TNFAIP8, tumor necrosis factor α-induced protein 8; MAPK, mitogen-activated protein kinase; CDDP, Cis-diamminedichloroplatinum

TNFAIP8 promotes AML chemoresistance by activating ERK signaling pathway through interaction with Rac1

“…Understanding the functional mechanism of TNFAIP8 in AML would greatly facilitate development of targeted therapy. Although the role of TNFAIP8 in negative regulation of apoptosis in malignancies have been well documented, the mechanisms by which TNFAIP8 functions vary among different cancer types and cell contexts [17][18][19][20][21][22][23][24][25]. Our study interpreted a previously unknown link between TNFAIP8 and ERK.…”

“…Tumor necrosis factor α-induced protein 8 (TNFAIP8), also called SCC-S2, GG2-1, MDC-3.13, NDED and OXIα, containing a death effector domain, was first found in human head and neck squamous cell carcinoma [17]. Its aberrant expression has been successively validated in cancers of breast, esophagus, lung, ovary, stomach and others [17][18][19][20][21][22][23][24][25]. Subsequent research provided insight into the regulatory function of TNFAIP8 in cell apoptotic network.…”

“…Subsequent research provided insight into the regulatory function of TNFAIP8 in cell apoptotic network. TNFAIP8 is capable of suppressing apoptosis by inhibiting caspase activation, thus promoting cisplatin resistance in cervical carcinoma [ 24 ]. In addition, TNFAIP8 has been reported to promote p53 ubiquitination and decrease p53-dependent pro-apoptotic responses, promoting drug resistance to cisplatin and doxorubicin of NSCLC cells, respectively [ 21 , 23 ].…”

Expression of TIPE family members in human colorectal cancer

“…TNFAIP8 interacts with large tumor suppressor kinase 1, regulates Hippo signaling in lung and liver cancer cells, and induces cell proliferation, migration and invasion ( 38 ). In addition, depletion of TNFAIP8 in HeLa cervical cancer cells activates caspase-3/8, induces p38 phosphorylation and promotes cisplatin-induced apoptosis and cell death ( 39 ). As for upstream regulators, the expression level of TNFAIP8 can be upregulated by NF-κB and TNF-α in diversified cell lines ( 40 ).…”

Role of CC Chemokines Subfamily in the Platinum Drugs Resistance Promotion in Cancer

“…Finally, recent investigations associate epigenetic regulations as potential resistance mechanisms (21), with cisplatin resistance regulated by microRNAs and methylation/demethylation of genes such as FANCF in ovarian cancer, and related to cytokines/chemokines (axis CXCL12-CXCR4) (8) to be studied in detail later in the review. Examples of reported tumors developing resistance to cisplatin are ovarian cancer (22,23) usually developed during treatment (acquired resistance) (24), cervical (25,26), lung (27,28), and gastric cancer (29,30); the last two can also develop intrinsic resistance, occurring when the drug is ineffective from the beginning of treatment (14,31).…”