Alpsoy Aktan, Gündüz Ufuk
Department of Biological Sciences, Middle East Technical University, 06800, Ankara, Turkey.
Tumour Biol. 2015 Jun;36(6):4417-26. doi: 10.1007/s13277-015-3081-3. Epub 2015 Jan 21.
Success of chemotherapy is generally impaired by multidrug resistance, intrinsic resistance, or acquired resistance to functionally and structurally irrelevant drugs. Multidrug resistance emerges via distinct mechanisms: increased drug export, decreased drug internalization, dysfunctional apoptotic machinery, increased DNA damage repair, altered cell cycle regulation, and increased drug detoxification. Several reports demonstrated that multidrug resistance is a multifaceted problem such that multidrug resistance correlates with increased aggressiveness and metastatic potential. Here, we tested the involvement of protein kinase D2, a serine/threonine kinase that was previously implicated in proliferation, drug resistance, and motility in doxorubicin-resistant MCF7 (MCF7/DOX) cell line, which served as an in vitro model for drug resistance and invasiveness. We showed that basal level activity of protein kinase D2 (PKD2) was higher in MCF7/DOX cells than parental MCF7 cells. To elucidate the roles of PKD2 MCF7/DOX, PKD2 expression was reduced via small interfering RNA (siRNA)-mediated knockdown. Results showed that acquired resistance of MCF7/DOX to doxorubicin was not affected by PKD2 silencing, while motility of MCF7/DOX cells was reduced. The results implied that PKD2 silencing might inhibit migration of MCF7/DOX cells without affecting chemoresistance significantly.
化疗的成功通常会受到多药耐药性、固有耐药性或对功能和结构无关药物的获得性耐药性的影响。多药耐药性通过不同机制出现：药物外排增加、药物内化减少、凋亡机制功能失调、DNA损伤修复增加、细胞周期调控改变以及药物解毒增加。一些报告表明，多药耐药性是一个多方面的问题，多药耐药性与侵袭性增加和转移潜能相关。在此，我们测试了蛋白激酶D2（一种丝氨酸/苏氨酸激酶，先前被认为与多柔比星耐药的MCF7（MCF7/DOX）细胞系的增殖、耐药性和运动性有关）的作用，该细胞系用作耐药性和侵袭性的体外模型。我们发现，MCF7/DOX细胞中蛋白激酶D2（PKD2）的基础水平活性高于亲本MCF7细胞。为了阐明PKD2在MCF7/DOX中的作用，通过小干扰RNA（siRNA）介导的敲低降低了PKD2的表达。结果表明，MCF7/DOX对多柔比星的获得性耐药性不受PKD2沉默的影响，而MCF7/DOX细胞的运动性降低。结果表明，PKD2沉默可能会抑制MCF7/DOX细胞的迁移，而不会显著影响化疗耐药性。
