Taylor Jackson R, Lehmann Brian D, Chappell William H, Abrams Stephen L, Steelman Linda S, McCubrey James A
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC 27858 USA.
Oncotarget. 2011 Aug;2(8):610-26. doi: 10.18632/oncotarget.315.
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.
逃避细胞衰老诱导是一种导致化疗耐药的重要机制。他莫昔芬去除雌激素信号或化疗药物阿霉素诱导的DNA损伤积累可在乳腺癌细胞系中诱导细胞衰老。在阿霉素中对激素敏感的乳腺癌细胞系MCF-7进行长期培养（MCF-7/DoxR）降低了阿霉素而非他莫昔芬诱导衰老的能力。在化疗和激素耐药中经常上调的两条信号通路是PI3K/PTEN/Akt/mTOR和Ras/Raf/MEK/ERK信号通路。为了确定活性Akt-1和Raf-1是否能影响药物诱导的衰老，我们将激活的ΔAkt-1(CA)和ΔRaf-1(CA)稳定导入药物敏感和阿霉素耐药细胞中。组成型活性Raf-1构建体的表达导致更高的基础衰老水平，表明这些细胞具有经历癌基因诱导衰老的能力。Akt信号通路的组成型激活显著降低了MCF-7细胞对阿霉素而非他莫昔芬的药物诱导衰老反应。然而，在含有高水平活性ERK的耐药细胞中组成型激活Akt-1可使其完全逃避阿霉素和他莫昔芬诱导的细胞衰老。这些结果表明，在Ras/Raf/MEK/ERK信号升高的情况下，Ras/PI3K/PTEN/Akt/mTOR信号通路的上调可通过减少化疗诱导的细胞衰老来促进耐药。了解含有某些致癌突变的乳腺癌如何逃避化疗和激素治疗诱导的细胞衰老，可能为设计更有效的乳腺癌治疗药物组合提供思路。
