BackgroundEGFR, a receptor tyrosine kinase (RTK), is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of many cancers, including NSCLC. However, intrinsic and acquired resistance to TKI remains a common obstacle. One strategy that may help overcome EGFR-TKI resistance is to target EGFR for degradation. As EGFR is a client protein of heat-shock protein 90 (HSP90) and sulforaphane is known to functionally regulate HSP90, we hypothesized that sulforaphane could attenuate EGFR-related signaling and potentially be used to treat NSCLC.ResultsOur study revealed that sulforaphane displayed antitumor activity against NSCLC cells both in vitro and in vivo. The sensitivity of NSCLC cells to sulforaphane appeared to positively correlate with the inhibition of EGFR-related signaling, which was attributed to the increased proteasomal degradation of EGFR. Combined treatment of NSCLC cells with sulforaphane plus another HSP90 inhibitor (17-AAG) enhanced the inhibition of EGFR-related signaling both in vitro and in vivo.ConclusionsWe have shown that sulforaphane is a novel inhibitory modulator of EGFR expression and is effective in inhibiting the tumor growth of EGFR-TKI-resistant NSCLC cells. Our findings suggest that sulforaphane should be further explored for its potential clinical applications against NSCLC.
Tid1, a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 is composed of 12 exons separated by 11 introns. Two alternatively spliced forms of Tid1 are expressed in humans, Tid1‐L and Tid1‐S. The Tid1‐S is generated by splicing of exon 10 to exon 12. Overexpression of Tid1‐S and Tid1‐L has been shown to produce opposing effects: cell death is repressed by Tid1‐S and enhanced by Tid1‐L. However, the mechanism of alternative splicing regulators to Tid1 isoforms development has been largely unknown. Heterogeneous nuclear ribonucleoproteins (hnRNPs) constitute a large family of proteins that associate with nascent pre‐mRNAs, packaging them into hnRNP particles. The A/B subfamily of hnRNPs (hnRNP A/Bs) are the most abundant hnRNPs in the nucleus. hnRNP A2/B1 is critical for precursor messenger RNA splicing. In this study, we tested the postulation that hnRNP A2/B1 may regulate alternative splicing of Tid1 isoforms. Our preliminary results indicated that knockdown of hnRNP A2/B1 in acute T cell leukemia‐derived Jurkat cells and lung cancer cells increased the expression of Tid1‐L gene and protein. Moreover, knockdown of hnRNP A2 produced a significant inhibition of cellular proliferation in Jurkat cells. These results suggest that specific knockdown for hnRNP A2/B1 decreases exclusion of exons 11 of Tid1 pre‐mRNA and influence cell proliferation of human cancer cells.
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