Abstract
BackgroundThe tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds.MethodsHuman non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle.ResultsAmong the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR.ConclusionsOur data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.
Highlights
The tyrosine kinase Src is involved in the progression of many cancers
Effects of AC-93253 iodide on the expression of proteins downstream from Src Src activity can affect the expression of many downstream proteins, including signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3K), JNK, Paxillin, p130cas, MEK, and ERK [28]; we investigated whether AC-93253 iodide influences the expression of any of these proteins
We found that co-treatment with AC-93253 iodide and MG132 can at least partially restore Src, EGFR, STAT3, and focal adhesion kinase (FAK) expression levels compared with treatment with AC-93253 iodide alone (Fig. 6b)
Summary
The tyrosine kinase Src is involved in the progression of many cancers. inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds. Oncogenic driver mutations are often the cause of normal cell functional dysregulation Most of these mutations occur in signal transduction-related kinases, including HER2, KRAS, AKT1, MEK, and EGFR, and they cause constitutive kinase activation, thereby inducing aberrant cancer cell growth and metastasis, which lead to poor prognoses and poor patient treatment responses [3, 4]. In the past few years, targeted therapies intended to treat lung cancer patients with certain driver mutations have been developed. The results of a previous study indicated that EGFR T790M mutations can lead to TKI resistance and are positively associated with lung cancer recurrence [8]. Drug resistance is a critical issue with respect to cancer treatment; developing new therapeutic strategies or new targeted drugs, including second-generation TKIs, exemplified by afatinib [9], and third-generation TKIs, including AZD9291 (osimertinib) [10], has become a main objective of the current studies focusing on cancer treatment
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