ING5 knockdown enhances migration and invasion of lung cancer cells by inducing EMT via EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways

Abstract

ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family, whose functions have been involved in the regulation of chromatin remodeling, cell cycle progression, proliferation and apoptosis. Our previous study has shown that ING5 overexpression inhibits lung cancer aggressiveness via suppressing epithelial to mesenchymal transition (EMT). However, the mechanisms remain largely unknown. In the current study, by Phospho-Kinase array and western blot, we have defined significantly upregulated EGFR/PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways in ING5 knockdown A549 cells, which could be downregulated by ING5 overexpression. PI3K inhibitor ZSTK474 or STAT3 inhibitor Niclosamide not only abolished ING5 knockdown-promoted proliferation, colony formation, migration and invasion of lung cancer A549 cells, but also impaired ING5 knockdown-stimulated metastasis of cancer cells in mouse xenograft models with tail vein injection of A549 cells. Furthermore, treatment with ZSTK474 or Niclosamide decreased protein level of EGFR, p-Akt, IL-6 and p-STAT3, and reversed ING5 knockdown-promoted EMT, as indicated by downregulated expression of EMT marker E-cadherin, an epithelial marker, increased expression of N-cadherin, a mesenchymal marker, and EMT-related transcription factors including Snail, Slug, Smad3 and Twist. Taken together, these results demonstrate that loss of ING5 enhances aggressiveness of lung cancer cells by promoting EMT via activation of EGFR/PI3K/Akt and IL-6/STAT3 signaling pathways.

A new niclosamide derivatives‐B17 can inhibit urological cancers growth through apoptosis‐related pathway

“…Many studies have reported on the niclosamide enhances cytotoxicity on various cancers, including oral cancer, lung cancer, colon, thyroid, cervix, ovarian, kidney, and prostate cancers, via STAT3, EGFR/PI3K/Akt, RANKL Wnt, mTOR, HIF‐1α/VEGF, Ras, c‐myc, and Notch signal pathways and mitochondria dysfunction 11, 12, 13, 14, 26, 27, 28, 29, 30, 31, 32, 33. Cancer cell upregulates other important downstream genes such as STAT3, which contributes to cell proliferation, cell survival, and angiogenesis in many cancers.…”

DNA damage and tissue repair: What we can learn from planaria

“…4A). Members of the ING family have been found to negatively regulate EGFR/PI3K/Akt signaling pathway, which is central to planaria neoblast re-population post IR [91,114]. Thus, the increased amount of IR-induced DNA damage together with upregulation of ING expression may act together to eliminate neoblast and prevent residual cell proliferation post-IR.…”

ING5 inhibits lung cancer invasion and epithelial–mesenchymal transition by inhibiting the WNT/β‐catenin pathway

“…Recently, the results of our studies and those of others have revealed that ING5 inhibits tumor progression and metastasis in lung, gastric, and breast cancers by inhibiting EMT. Using protein array, we have screened and confirmed that activation of both IL‐6/STAT3 and EGFR/PI3K/Akt signaling pathways is involved in ING5 knockdown‐promoted lung cancer invasiveness and EMT …”

“…Using protein array, we have screened and confirmed that activation of both IL-6/STAT3 and EGFR/PI3K/Akt signaling pathways is involved in ING5 knockdown-promoted lung cancer invasiveness and EMT. 14 Apart from PI3K/Akt and STAT3 oncogenic signaling pathways, hyperactivation of Wnt/β-catenin signaling is widely implicated in many types of cancers. 15,16 Our previous protein array results showed an increased β-catenin level in ING5 knockdown A549 cells, 14 suggesting that ING5 may also affect the β-catenin signaling pathway.…”