Sulforaphane attenuates EGFR signaling in NSCLC cells

Abstract

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.

Development of a Novel Experimental In Vitro Model of Isothiocyanate-induced Apoptosis in Human Malignant Melanoma Cells

“…The majority of studies have utilized non-melanoma (8)(9)(10)(11)(12)(13)(14) and melanoma (15)(16)(17)(18)(19) experimental models based on a single bolus addition of large ITC concentrations where a wide range of biological effects were documented but without provision of appropriate control (non-tumorigenic) cells. Similarly, we have been able to document such anticancer activity in melanoma cells but also in control keratinocyte cells suggesting a non-specific potency towards any type of cell line (tumorigenic or not).…”

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3β/β-catenin signaling pathways

“…However, the effect of sulforaphane on lung cancer metastasis, which limits the lifespan of lung cancer patients, has not been explored. The attenuation of the EGFR signal pathway by sulforaphane suggests a mechanism for the potential anti-metastatic effects of the drug in non-small cell lung cancers (NSCLCs) [7] . MicroRNAs (miRNAs), which function as negative regulator of gene expression, are involved in various biological functions, including development and differentiation, metabolism, immune response, proliferation, apoptosis and metastasis.…”

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“…SFN induces apoptosis via caspase-dependent pathways on malignant glioma and to shrink tumor size. Daily injection of SFN in a xenograft immune deficient mouse model showed a decrease in mean tumor weight of up to 75% compared to controls [69]. In other types of cancers including non-small cell lung cancer, SFN has been shown to not only induce apoptosis but also to inhibit metastasis and progression as well [70].…”