Venkatesh Jaganathan, Rishi Arun K, Reddy Kaladhar B
John D. Dingell VA Medical Center, Wayne State University, Detroit, MI, USA.
Department of Oncology, Wayne State University, Detroit, MI, USA.
Genes Cancer. 2020 Jul 22;11(3-4):95-105. doi: 10.18632/genesandcancer.204. eCollection 2020 Dec 31.
Previous studies from our group and others have shown that current drug treatment(s) strategies eliminate bulk of tumor cells (non-CSCs) but it had a minimal effect on cancer stem cells (CSCs) leading to resistance and tumor recurrence. We studied the effects of CFM-4.16 (CARP-1 functional mimetic) and/or cisplatin on four Triple-negative breast cancer (TNBC) MDA-MB-468, MDA-MB-231, CRL-2335 and BR-1126, two cisplatin resistant CisR/MDA-231 and CisR/MDA-468 and cancer stem cells (CSCs) from resistant cell lines. TNBC cells treated with CFM-4.16 plus cisplatin inhibited the expression of FZD8, LRP6 and c-Myc and significantly enhanced cell death in all the cell lines by ~70%-80% compared with the control(s). When Cisplatin resistant CisR/MDA-231 and CisR/MDA-468 were treated with CFM-4.16 plus cisplatin, they also showed a reduction in FZD8 and LRP6 and increased apoptosis compared to control group. Similarly, CFM-4.16 plus cisplatin treatment reduced mammospheres formation abilities of CSCs by 80-90% compared to control group, increased PARP cleavage and apoptosis. Data shows CFM-4.16 plus cisplatin treatment significantly increased apoptosis/cell death in parental, cisplatin resistant and CSCs. Taken together the data suggests that FZD8-mediated Wnt-signaling plays a major role in mediating CSCs growth and resistance to chemotherapy and its inhibition enhances the chemotherapeutic response in TNBC.
我们团队及其他团队之前的研究表明，当前的药物治疗策略可消除大部分肿瘤细胞（非癌症干细胞），但对癌症干细胞（CSCs）的影响极小，从而导致耐药性和肿瘤复发。我们研究了CFM-4.16（CARP-1功能模拟物）和/或顺铂对四种三阴性乳腺癌（TNBC）细胞系MDA-MB-468、MDA-MB-231、CRL-2335和BR-1126、两种顺铂耐药细胞系CisR/MDA-231和CisR/MDA-468以及耐药细胞系中的癌症干细胞（CSCs）的影响。与对照组相比，用CFM-4.16加顺铂处理的TNBC细胞抑制了FZD8、LRP6和c-Myc的表达，并在所有细胞系中显著增强细胞死亡，增幅约为70%-80%。当用CFM-4.16加顺铂处理顺铂耐药的CisR/MDA-231和CisR/MDA-468时，与对照组相比，它们的FZD8和LRP6也有所减少，且凋亡增加。同样，与对照组相比，CFM-4.16加顺铂处理使CSCs的乳腺球形成能力降低了80%-90%，增加了PARP裂解和凋亡。数据表明，CFM-4.16加顺铂处理显著增加了亲代细胞、顺铂耐药细胞和CSCs中的凋亡/细胞死亡。综上所述，数据表明FZD8介导的Wnt信号在介导CSCs生长和化疗耐药中起主要作用，对其抑制可增强TNBC的化疗反应。
