Abstract
Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
Highlights
The epidermal growth factor receptor (EGFR) overexpresses and activates the downstream phosphoinositide 3-kinase-AKT and mitogen-activated protein kinase-extracellular signalregulated kinase (ERK; MEK) signaling pathways, respectively, regulating the survival and proliferation of cancer cells [1,2]
We further identified the stemness characteristics in the formed tumorspheres through quantitative reverse transcription polymerase chain reaction (PCR) by measuring the expression of cancer stemness markers, namely Aldehyde dehydrogenase 1 (Aldh1), Cd133, Oct4, and Nanog
To compare the cytotoxic capacity of YM155 against tumorsphere formation and parental cell lines, YM155 was applied to HCC827 and A549 cells in the stemness cultured or integrated medium. (A) YM155 significantly reduced HCC827 cells when used at a dose of 100 ng/mL (**p < 0.01) and (B) A549 cells when used at a dose of 1 ng/mL (***p < 0.001). (C) Microscopy revealed that 10 ng/mL of YM155 considerably inhibited the formation of HCC827 and (D) A549CSC tumorspheres and resulted in a lower cell viability. (E) Because EGFR overexpresses in HCC827 and A549 cells, and because YM155 has been reported to suppress EGFR, we investigated the autophosphorylation status of EGFR in HCC827- and A549-derived tumorspheres
Summary
The epidermal growth factor receptor (EGFR) overexpresses and activates the downstream phosphoinositide 3-kinase-AKT and mitogen-activated protein kinase-extracellular signalregulated kinase (ERK; MEK) signaling pathways, respectively, regulating the survival and proliferation of cancer cells [1,2]. EGFR overexpression exceeds 90% in lung cancer, acting as a target for potent therapeutic agents. We hypothesized that EGFR participates in maintaining the cancer stemness property as the leading cause of tumor recurrence. We investigated the detailed molecular mechanisms of YM155 as a potent inhibitor of cancer stemness cells (CSCs). The structure of YM155 is similar to that of a stemness inhibitor, BBI608 [7,8]. This evidence reveals that YM155 is a potent agent against lung cancer stemness. YM155 inhibits anti-apoptosis by suppressing ILF3-mediated survivin, its detailed mechanism in the inhibition of cancer stemness is unclear
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