Primaquine Inhibits the Endosomal Trafficking and Nuclear Localization of EGFR and Induces the Apoptosis of Breast Cancer Cells by Nuclear EGFR/Stat3-Mediated c-Myc Downregulation.

Ji-Hyang Kim,Dong-Sun Lee,Hack-Sun Choi

doi:10.3390/ijms222312961

Ji-Hyang Kim, Dong-Sun Lee + Show 1 more

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https://doi.org/10.3390/ijms222312961

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Abstract

Triple-negative breast cancer (TNBC) cells overexpress the epidermal growth factor receptor (EGFR). Nuclear EGFR (nEGFR) drives resistance to anti-EGFR therapy and is correlated with poor survival in breast cancer. Inhibition of EGFR nuclear translocation may be a reasonable approach for the treatment of TNBC. The anti-malarial drugs chloroquine and primaquine have been shown to promote an anticancer effect. The aim of the present study was to investigate the effect and mechanism of chloroquine- and primaquine-induced apoptosis of breast cancer cells. We showed that primaquine, a malaria drug, inhibits the growth, migration, and colony formation of breast cancer cells in vitro, and inhibits tumor growth in vivo. Primaquine induces damage to early endosomes and inhibits the nuclear translocation of EGFR. Primaquine inhibits the interaction of Stat3 and nEGFR and reduces the transcript and protein levels of c-Myc. Moreover, primaquine and chloroquine induce the apoptosis of breast cancer cells through c-Myc/Bcl-2 downregulation, induce early endosome damage and reduce nEGFR levels, and induce apoptosis in breast cancer through nEGFR/Stat3-dependent c-Myc downregulation. Our study of primaquine and chloroquine provides a rationale for targeting EGFR signaling components in the treatment of breast cancer.

Highlights

Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression and accounts for 15% to 20% of breast cancers [1]
The antineoplastic mechanism of primaquine was previously unclear, but here we have shown a new mechanism of primaquine: it exerts anticancer effects through nuclear EGFR (nEGFR) downregulation (Figures 1 and 3)
As primaquine induced the apoptosis of breast cancer, we wanted to identify the apoptotic mechanism of primaquine

Summary

Introduction

Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression and accounts for 15% to 20% of breast cancers [1]. NEGFR, as a molecular target in cancer, functions as a cotranscription factor for the expression of several oncogenes: cyclin D1, inducible nitric oxide synthase (iNOS), B-Myb, Aurora kinase A, cyclooxygenase 2 (COX2), c-Myc, breast cancer resistance protein (BCRP), and signal transducer and activator of transcription 1 (Stat1) [15,16,17,18,19,20,21]. The nuclear translocation of EGFR reduces the inhibitory effects of cetuximab and confers AXL RTK-mediated cetuximab resistance through the activation of downstream signaling [5,10]

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