Inhibition of the PLK1-Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer.
Inhibition of the PLK1-Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer.
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抑制 PLK1 偶联的细胞周期机制可克服结直肠癌对奥沙利铂的耐药性
DOI：
10.1002/advs.202100759
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Yu Z;Deng P;Chen Y;Liu S;Chen J;Yang Z;Chen J;Fan X;Wang P;Cai Z;Wang Y;Hu P;Lin D;Xiao R;Zou Y;Huang Y;Yu Q;Lan P;Tan J;Wu X
细胞周期机制的失调导致基因组不稳定，是结直肠癌(CRC)中与化疗耐药和预后不良相关的癌症的标志。识别和靶向异常的细胞周期机制有望改善目前对结直肠癌患者的治疗。在这里，发现结直肠癌中上调的Polo-like kinase1(PLK1)信号，伴随着细胞周期相关通路的失控。研究表明，PLK1信号的异常与结直肠癌的复发和预后不良有关。在体内外，PLK1的遗传和药物阻断显著增加了对奥沙利铂的敏感性。从机制上讲，转录图谱分析显示，细胞周期相关通路被奥沙利铂处理激活，但被PLK1抑制剂抑制。细胞分裂周期7(CDC7)进一步被认为是PLK1信号的关键下游效应因子，通过PLK1-MYC轴反式激活。在结直肠癌中，CDC7的高表达与PLK1信号的异常呈正相关，并与预后不良有关。此外，CDC7抑制剂协同增强了奥沙利铂在结直肠癌模型中的抗肿瘤作用，显示了靶向PLK1-MYC-CDC7轴在奥沙利铂为主的化疗中的潜在用途。PLK1-MYC-CDC7轴的高活性与结直肠癌的复发和预后不良有关。这一轴的遗传和药物阻断在体内外显著增加了奥沙利铂的敏感性，为PLK1或CDC7抑制剂联合化疗方案治疗结直肠癌提供了潜在的临床优势。
Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo‐like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle‐related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle‐related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1‐MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti‐tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1‐MYC‐CDC7 axis in the treatment of oxaliplatin‐based chemotherapy. Hyperactivity of PLK1‐MYC‐CDC7 axis correlates with recurrence and poor prognosis in colorectal cancer. Genetic and pharmacological blockade of this axis significantly increases the sensitivity to oxaliplatin in vitro and in vivo, providing potential clinical advantage in using PLK1 or CDC7 inhibitor in combination with chemotherapy regimens in treatment of CRC patients.
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影响因子：
5.7
作者：
Gutteridge RE;Ndiaye MA;Liu X;Ahmad N
通讯作者：
Ahmad N
PLK1的过表达诱导染色体不稳定性并抑制肿瘤的发育。
影响因子：
16.6
作者：
de Cárcer G;Venkateswaran SV;Salgueiro L;El Bakkali A;Somogyi K;Rowald K;Montañés P;Sanclemente M;Escobar B;de Martino A;McGranahan N;Malumbres M;Sotillo R
通讯作者：
Sotillo R
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
3.7
作者：
Lin HX;Qiu HJ;Zeng F;Rao HL;Yang GF;Kung HF;Zhu XF;Zeng YX;Cai MY;Xie D
通讯作者：
Xie D
影响因子：
20.3
作者：
Doehner, Hartmut;Luebbert, Michael;Maertens, Johan
通讯作者：
Maertens, Johan