Abstract
BackgroundThe five-year survival rates for head and neck squamous cell carcinoma (HNSCC) patients are less than 50%, and the prognosis has not improved, despite advancements in standard multi-modality therapies. Hence major emphasis is being laid on identification of novel molecular targets and development of multi-targeted therapies. 14-3-3 zeta, a multifunctional phospho-serine/phospho-threonine binding protein, is emerging as an effector of pro-survival signaling by binding to several proteins involved in apoptosis (Bad, FKHRL1 and ASK1) and may serve as an appropriate target for head and neck cancer therapy. Herein, we determined effect of guggulsterone (GS), a farnesoid X receptor antagonist, on 14-3-3 zeta associated molecular pathways for abrogation of apoptosis in head and neck cancer cells.MethodsHead and neck cancer cells were treated with guggulsterone (GS). Effect of GS-treatment was evaluated using cell viability (MTT) assay and apoptosis was verified by annexin V, DNA fragmentation and M30 CytoDeath antibody assay. Mechanism of GS-induced apoptosis was determined by western blotting and co-IP assays using specific antibodies.ResultsUsing in vitro models of head and neck cancer, we showed 14-3-3 zeta as a key player regulating apoptosis in GS treated SCC4 cells. Treatment with GS releases BAD from the inhibitory action of 14-3-3 zeta in proliferating HNSCC cells by activating protein phosphatase 2A (PP2A). These events initiate the intrinsic mitochondrial pathway of apoptosis, as revealed by increased levels of cytochrome c in cytoplasmic extracts of GS-treated SCC4 cells. In addition, GS treatment significantly reduced the expression of anti-apoptotic proteins, Bcl-2, xIAP, Mcl1, survivin, cyclin D1 and c-myc, thus committing cells to apoptosis. These events were followed by activation of caspase 9, caspase 8 and caspase 3 leading to cleavage of its downstream target, poly-ADP-ribose phosphate (PARP).ConclusionGS targets 14-3-3 zeta associated cellular pathways for reducing proliferation and inducing apoptosis in head and neck cancer cells, warranting its investigation for use in treatment of head and neck cancer.
Highlights
The five-year survival rates for head and neck squamous cell carcinoma (HNSCC) patients are less than 50%, and the prognosis has not improved, despite advancements in standard multi-modality therapies
Various mechanisms have been proposed to explain the anti-carcinogenic effects of GS, including inhibition of reactive oxygen species (ROS), suppression of inflammation and inhibition of nuclear receptors, transcription factors [nuclear factor kappa B (NFB), signal transducer and activator of transcription 3 (STAT3)], anti-apoptotic (Bcl-2, Bax, Bad and xIAP) and cell cycle-regulatory proteins (p21, p16 and cyclin D1)
We investigated the effect of GS on 14-3-3 zeta and its role in GS-induced apoptosis in HNSCC cells
Summary
The five-year survival rates for head and neck squamous cell carcinoma (HNSCC) patients are less than 50%, and the prognosis has not improved, despite advancements in standard multi-modality therapies. We determined effect of guggulsterone (GS), a farnesoid X receptor antagonist, on 14-3-3 zeta associated molecular pathways for abrogation of apoptosis in head and neck cancer cells. GS has been reported to induce apoptosis, suppress proliferation, invasion, angiogenesis and metastasis in a wide variety of human cancer cell lines, including acute myeloid leukemia, head and neck, prostate, lung, breast, colon and ovarian cancer [13,14,15,16,17,18,19,20,21,22]. In our earlier reports, we demonstrated GS reduced the levels of pSTAT3 (p-tyr-705) in both multiple myeloma and HNSCC cell lines [24]
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