Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells

Abstract

We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3, and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration, and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and Janus kinases (Jaks), aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF), and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility, and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared to the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small-intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer.

Regulation of cell migration via the EGFR signaling pathway in oral squamous cell carcinoma cells

“…This directed cell migration is often regulated by responses to extracellular stimuli (33)(34)(35). Notably, signal transduction via EGFR has an important role in cell motility in various types of cancer (36,37). In the present study, EGF-EGFR signaling was identified to be required for the migration of SAS OSCC cells, but not for HSC4 OSCC cells.…”

Effects of general anesthesia with or without epidural block on tumor metastasis and mechanisms

“…Additionally, expression of EGFR is altered in a variety of human cancer types, including carcinoma of the lung, breast, head and neck, ovary and bladder, as well as in glioma (35)(36)(37). STAT3 and EGFR serve notable roles in tumor development and metastasis (34,38). The results of the present study indicated that GEA significantly inhibited tumor metastasis by reducing levels of p-STAT3 and p-EGFR.…”

“…3). The levels of p-STAT3 and p-EGFR in group G were slightly lower than those in group C. It was shown that there were significantly (P<0.05) lower levels of p-STAT3 and p-EGFR in group G + E than in groups C and G. Evidence indicates that aberrant STAT3 signaling promotes the initiation and progression of human cancer by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion and metastasis (32)(33)(34). Additionally, expression of EGFR is altered in a variety of human cancer types, including carcinoma of the lung, breast, head and neck, ovary and bladder, as well as in glioma (35)(36)(37).…”

Review: Mechanotransduction in ovarian cancer: Shearing into the unknown

“…[119][120][121] EMT is an important part of ovarian cancer progression, in which free floating spheroids attach to the mesothelium, disseminate and metastasize to surrounding tissues. 122,123 Expression of CD44 and CA125, high levels of IL-6, CXR4, and CXCL12 and the amplification of PIK3CA, Akt and bone morphogenetic protein (BMP) pathways have been associated with ovarian cancer EMT. 17,124,125 The review by Tan et al provides an in-depth look at epithelial ovarian cancer metastasis.…”