Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.
Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, People's Republic of China.
Curr Cancer Drug Targets. 2023;23(4):293-306. doi: 10.2174/1568009622666220616122846.
Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC.
We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo.
KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo.
This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.
迫切需要新的治疗策略来改善胃癌（GC）的临床结果。KIF15 与 KIF11 合作促进双极纺锤体的组装和形成，这对于正确的姐妹染色单体分离至关重要。因此，我们推测联合抑制 KIF11 和 KIF15 可能是治疗 GC 的有效策略。因此，为了验证这一假设，我们旨在评估 KIF15 抑制剂 KIF15-IN-1 和 KIF11 抑制剂伊匹尼布在 GC 中的联合治疗效果。
我们使用免疫组织化学和免疫印迹法验证了 KIF11 和 KIF15 在 GC 组织中的表达。接下来，我们确定了 KIF11 或 KIF15 敲除对 GC 细胞系增殖的影响。最后，我们研究了 KIF11 和 KIF15 抑制剂在体外和体内的联合作用。
KIF11 和 KIF15 在 GC 组织中的表达高于相邻正常组织。KIF11 或 KIF15 的敲除均抑制了 GC 细胞的增殖和克隆形成能力。我们发现，KIF15 敲除显著增加了 GC 细胞对伊匹尼布的敏感性，而其过表达则表现出相反的效果。此外，使用 KIF15-IN-1 和伊匹尼布联合使用对 GC 的抗肿瘤增殖具有协同作用，无论是在体外还是体内。
这项研究表明，抑制 KIF11 和 KIF15 的联合治疗可能是一种有效的治疗胃癌的策略。
