Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells.
Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells.
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DOI：
10.18632/oncotarget.315
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发表时间：
2011-08
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影响因子：
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通讯作者：
McCubrey JA
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文献类型：
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作者：
Taylor JR;Lehmann BD;Chappell WH;Abrams SL;Steelman LS;McCubrey JA
逃避细胞衰老诱导是化学抗性的一种有效机制。乳腺癌细胞系中的细胞衰老可以通过用他莫昔芬去除雌激素信号传导或通过化疗药物阿霉素诱导的DNA损伤的积累来诱导。在阿霉素中长期培养对阿霉素敏感的乳腺癌细胞系MCF-7（MCF-7/DoxR）降低了阿霉素诱导衰老的能力，但没有他莫昔芬。在化疗和化疗耐药性中经常上调的两种途径是PI3K/PTEN/Akt/mTOR和Ras/Raf/MEK/ERK途径。为了确定激活的Akt-1和Raf-1是否可以影响药物诱导的衰老，我们将激活的Δ Akt-1（CA）和Δ Raf-1（CA）稳定地引入药物敏感和多柔比星耐药细胞中。组成型活性Raf-1构建体的表达导致更高的基线衰老，表明这些细胞具有经历癌基因诱导的衰老的能力。在MCF-7细胞中，Akt通路的组成性激活显著降低了对多柔比星的药物诱导衰老，但对他莫昔芬没有影响。然而，在含有高水平活性ERK的耐药细胞中，组成性Akt-1活化完全逃脱了多柔比星和他莫昔芬诱导的细胞衰老。这些结果表明，在Ras/Raf/MEK/ERK信号传导一起升高的情况下，Ras/PI3K/PTEN/Akt/mTOR通路的上调可以通过减少响应于化疗的细胞衰老而有助于耐药性。了解含有某些致癌突变的乳腺癌如何逃避细胞衰老，以应对化疗和激素为基础的治疗可能会提供更有效的药物组合治疗乳腺癌的设计见解。
Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.