Modulation of Myb‐induced NF‐kB ‐STAT3 signaling and resulting cisplatin resistance in ovarian cancer by dietary factors

Abstract

c-Myb regulates tumorigenesis in multiple cancers. Here we show, for the first time, the mechanism of c-Myb-mediated proliferation, invasion, and drug resistance in ovarian cancer (OC), the most lethal gynecological cancer, and a comparative analyses of dietary agents, curcumin, epigallocatechin-3-gallate (EGCG), and sulforaphane in inhibiting c-Myb activity. We evaluated myb expression in patients with OC and found its increased expression in patients with cancer, compared with normal controls and in higher grade tumors, compared with low-grade tumors. Using ES2 and OVCAR3 cell line models, along with the silencing or overexpression of c-Myb, we establish a role of c-Myb in determining resistance to cisplatin. c-Myb overexpression activated NF-κB and STAT3 signaling leading to enhanced proliferation, invasion, and cisplatin resistance. Contrary to this, silencing of c-Myb inhibited proliferation, invasion, and sensitized OC cells to cisplatin. Further, among the dietary agents tested, EGCG almost completely inhibited the c-Myb-induced proliferation and invasion whereas sulforaphane also had significant inhibitory effect. Both compounds significantly sensitized OC cells to cisplatin, reversing the c-Myb effects. Higher c-Myb levels in patients with ovarian cancer lead to poor survival and our results indicate a possible effect of dietary factors EGCG and sulforaphane against c-Mybmediated ovarian cancer progression and chemoresistance.

PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin‑3‑gallate in ovarian cancer

“…However, the present study demonstrated that EGCG exerted a stronger proliferation inhibition on ovarian cancer SKOV3 cells compared with that on lung cancer A549 cells, although few studies (44,45) have focused on the effects of EGCG on ovarian cancer. Thus, it was meaningful and worthy to study the effects of EGCG on ovarian cancer and explore the underlying molecular mechanism.…”

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

“…However, c-Myb silencing inhibited proliferation, invasive potential, and sensitized ovarian cancer cells to cisplatin. EGCG completely inhibited c-Myb-mediated proliferative and invasive abilities of ovarian cancer cells [11].…”

“…There was higher expression of cytoplasmic STAT1, p-STAT3 (Ser727), STAT5, and nuclear p-STAT3 (Ser727) in the nodes [10]. c-Myb overexpression induced activation of NF-κB and STAT3 signaling to enhance proliferation, invasion, and resistance against cisplatin [11]. However, c-Myb silencing inhibited proliferation, invasive potential, and sensitized ovarian cancer cells to cisplatin.…”

Regulation of MYB mediated cisplatin resistance of ovarian cancer cells involves miR-21-wnt signaling axis

“…A protooncogene c-MYB was recently showed to contribute to cisplatin resistance in ovarian cancer 9 and these reported results were the first ever detailing the c-MYBs contribution to proliferation, invasion and development of cisplatin resistance in ovarian cancer cells. One of the key findings of this work was that c-MYB expression is relatively higher in ovarian cancer patients, as compared to normal controls, thus clearly suggesting a role of c-MYB in ovarian cancer pathogenesis.…”

“…Moreover, the expression of c-MYB correlated with higher grade ovarian cancer which suggested a direct relationship between c-MYB expression and aggressive ovarian cancer. The oncogenic role of c-MYB is not limited to ovarian cancer and has been reported in hematological malignancies as well as several solid tumors [9][10][11][12][13] , Despite such wealth of information regarding the oncogenic potential of c-MYB, its role in cisplatin resistance was not known prior to this report 9 . The study reported a connection between c-MYB expression and acquired cisplatin resistance, but there is still no clear understanding regarding how c-MYB can influence cisplatin resistance.…”