In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epitheli... - 0 views
-
we functionally validated a potent EOC oncogene, KPNB1, and showed its clinical relevance to human EOC
-
a well-established antiparasitic drug, ivermectin, has antitumor effects on EOC through its inhibition of KPNB1
- ...22 more annotations...
-
Sequencing revealed that almost all tumors (96%) had mutations in TP53, which serves as a major driver of this cancer
-
Low-prevalence but statistically significant mutations in nine other genes including NF1, BRCA1, BRCA2, RB1, and CDK12 were also identified, but the majority of genes were mutated at low frequency, making it difficult to distinguish between driver and passenger mutations
-
KPNB1 inhibition via any of three KPNB1 siRNAs or importazole treatment induced apoptosis in human EOC cell lines (Fig. 3 A–F and Fig. S4), and was accompanied by an increase in the expression levels of the proapoptotic proteins BAX and cleaved caspase-3
-
Stable overexpression of KPNB1 in SKOV3 and OVCAR3 (Fig. S6) significantly accelerated cell proliferation/survival (Fig. 5 A–C), confirming that KPNB1 functions as an oncogene in EOC
-
KPNB1 overexpression significantly decreased caspase-3/7 activity (Fig. 5D), in addition to the expression levels of cleaved caspase-3 and BAX proteins (Fig. 5E). KPNB1 overexpression also decreased p21 and p27 protein levels (Fig. 5E), as opposed to their increase by KPNB1 inhibition
-
Patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1
-
ivermectin treatment suppressed cell proliferation/viability in a dose-dependent manner (Fig. 7A), indicating that it exerts an antitumor effect on EOC
-
we found that ivermectin synergistically reduced cell proliferation/viability in combination with paclitaxel in human EOC cells
-
Single treatment of ivermectin or paclitaxel reduced tumor growth in nude mice, but, notably, combination treatment of ivermectin and paclitaxel almost completely suppressed tumor growth
-
ERBB2, is amplified and overexpressed in many cancers, including breast (31), ovary (31), colon (32), bladder (33), non-small-cell lung (34), and gastric cancer (35), and is a poor prognostic factor in certain cancer types
-
Increased KPNB1 protein levels have been reported in several cancers, including cervical cancer (42), hepatocellular carcinoma (43), and glioma (44), suggesting KPNB1’s oncogenic potential in these tumor types
-
our findings suggest that KPNB1 might serve as a master regulator of cell cycle by regulating several cell cycle-related proteins, including p21, p27, and APC/C family members
-
higher and/or more-frequent doses of ivermectin than currently approved for humans are well tolerated in humans
-
none of the mice in this study treated with the effective dosage of ivermectin for in vivo anticancer therapy showed severe adverse event
-
we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC cell lines than either drug alone