STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells

Abstract

In cervical cancer, p53-induced apoptosis is abrogated by human papilloma virus (HPV)-derived oncoprotein E6. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) provides tumor-specific apoptosis in various cancers, including cervical cancer, the sensitivity differs depending on the cell lines. Signal transducer and activator of transcription 3 (STAT3) is a hub molecule that shifts the cellular fate to apoptosis or survival in response to cellular stresses. However, the contribution of STAT3 activity to TRAIL-induced apoptosis in cervical cancer remains unknown. We examined the TRAIL sensitivity in cervical cancer cells, using TRAIL-resistant (SiHa) and -sensitive (CaSki) cervical cancer cell lines and focused on STAT3 function involving the apoptotic pathway. STAT3 was inactivated by TRAIL stimulation in the CaSki cell line, but not in the SiHa cell line. We then inhibited STAT3 expression in the SiHa cell line using siRNA against STAT3 and suppressed STAT3 activity using a STAT3 inhibitor; both these treatments sensitized TRAIL-induced apoptosis in the SiHa cell line. Furthermore, the SiHa cells were exposed to tunicamycin (TM), an endoplasmic reticulum (ER) stress inducer that inactivates STAT3, with or without TRAIL. Accompanied by STAT3 inactivation, TM pretreatment significantly enhanced TRAIL-induced apoptosis. We therefore concluded that TRAIL-induced apoptosis was regulated by STAT3 in response to TRAIL stimulation. Our results also suggest that STAT3 inhibition increases the sensitivity of malignancies, particularly HPV-related cancer, to TRAIL-based therapy.

Cyclin‐dependent kinase 9 promotes cervical cancer development via AKT2/p53 pathway

“…Multiple different genes including p53, BCL2, AKT2, and STAT3 have been reported to regulate apoptosis in cervical cancer (23,(32)(33)(34). The p53 family of proteins is central regulator of cell survival and apoptosis.…”

STAT3 activation in infection and infection-associated cancer

“…It has been found that activated STAT3 suppresses p53-mediated apoptosis by binding to the promoter of p53 and inhibiting the transcription of p53. STAT3 can promote tumor cell proliferation by up-regulating the expression of the cyclinB1/cdc-2/c-myc/cyclinD1/c-jun/c-fos complex and down-regulating the expression of the cyclinB1 kinase inhibitor CDK1 in p21/p27 expressing cells, which drives rapid progression through the G1/S checkpoint 59–61 .…”

Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 + cells in clear cell renal carcinoma

“…9 We refer to the CD133 + CSCs in our study as "cancer stem-like cells" because although previous studies have reported that CD133 + cells from several human tumors exhibit xenotransplantation potential in severe combined immunodeficiency (SCID) mice, 10,11 isolated CD133 + cells from human RCC tissue failed to form tumors when transplanted into SCID mice but instead, these cells potentiate tumor engraftment when cotransplanted with CD133 -RCC cells. 13 STAT proteins can be tyrosine, serine, and/or threonine phosphorylated. Significantly, CD133 expression has been suggested as a useful risk stratification tool in RCC.…”

“…12 Signal transducers and activators of transcription (STAT) exist as latent, un-phosphorylated monomers in the cytoplasm, and transmit signals from diverse cytokines and growth factors. 13 STAT proteins can be tyrosine, serine, and/or threonine phosphorylated. 14 The best-known pathway involves the Janus kinase (JAK)-mediated phosphorylation of tyrosine residues, inducing STAT dimerization and translocation into the nucleus where phosphorylated (p)STATs act as transcription factors.…”