Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer.
Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.
['Sexton|Rachel|R|', 'Mahdi|Zaid|Z|', 'Chaudhury|Rahman|R|', 'Beydoun|Rafic|R|', 'Aboukameel|Amro|A|', 'Khan|Husain Y|HY|', 'Baloglu|Erkan|E|', 'Senapedis|William|W|', 'Landesman|Yosef|Y|', 'Tesfaye|Anteneh|A|', 'Kim|Steve|S|0000-0001-9950-1232', 'Philip|Philip A|PA|', 'Azmi|Asfar S|AS|0000-0003-1178-9505']
D021581:Active Transport, Cell Nucleus D000970:Antineoplastic Agents D017209:Apoptosis D045744:Cell Line, Tumor D002467:Cell Nucleus D002470:Cell Survival D006801:Humans D028884:Karyopherins D017239:Paclitaxel D018160:Receptors, Cytoplasmic and Nuclear D013274:Stomach Neoplasms
XPO1/CRM1 gastric cancer SINE miRNA nuclear protein transport