Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death.
Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death.
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DOI：
10.1038/cddis.2017.225
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发表时间：
2017-06-01
影响因子：
9
通讯作者：
Wiman KG
中科院分区：
文献类型：
--
作者：
Cheteh EH;Augsten M;Rundqvist H;Bianchi J;Sarne V;Egevad L;Bykov VJ;Östman A;Wiman KG
耐药性是癌症治疗中的主要问题。越来越多的证据表明，肿瘤微环境，包括癌症相关成纤维细胞（CAF），可以调节肿瘤细胞的药物敏感性。我们研究了原代人CAF对用化疗药物治疗的前列腺癌细胞中的p53诱导和细胞活力的影响。与前列腺CAF或CAF条件培养基共培养可减弱DNA损伤和p53对化疗药物的反应，并提高前列腺癌细胞存活率。在前列腺癌细胞中，CAF条件培养基以与癌细胞谷胱甘肽水平增加相关的方式抑制多柔比星而不是紫杉醇的积累。低分子量部分（<3kDa）的CAF条件培养基具有相同的效果。CAF条件培养基还抑制阿霉素和紫杉醇处理的癌细胞中活性氧（ROS）的诱导。我们的研究结果表明，CAFs可以通过抑制药物积累和抵消药物诱导的氧化应激来增强癌细胞的耐药性。这种保护机制可能代表癌症的新治疗靶点。
Drug resistance is a major problem in cancer therapy. A growing body of evidence demonstrates that the tumor microenvironment, including cancer-associated fibroblasts (CAFs), can modulate drug sensitivity in tumor cells. We examined the effect of primary human CAFs on p53 induction and cell viability in prostate cancer cells on treatment with chemotherapeutic drugs. Co-culture with prostate CAFs or CAF-conditioned medium attenuated DNA damage and the p53 response to chemotherapeutic drugs and enhanced prostate cancer cell survival. CAF-conditioned medium inhibited the accumulation of doxorubicin, but not taxol, in prostate cancer cells in a manner that was associated with increased cancer cell glutathione levels. A low molecular weight fraction (<3 kDa) of CAF-conditioned medium had the same effect. CAF-conditioned medium also inhibited induction of reactive oxygen species (ROS) in both doxorubicin- and taxol-treated cancer cells. Our findings suggest that CAFs can enhance drug resistance in cancer cells by inhibiting drug accumulation and counteracting drug-induced oxidative stress. This protective mechanism may represent a novel therapeutic target in cancer.
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影响因子：
3.7
作者：
Hägglöf C;Hammarsten P;Josefsson A;Stattin P;Paulsson J;Bergh A;Ostman A
通讯作者：
Ostman A
影响因子：
5.6
作者：
Eder T;Weber A;Neuwirt H;Grünbacher G;Ploner C;Klocker H;Sampson N;Eder IE
通讯作者：
Eder IE
影响因子：
--
作者：
Hanigan, Marie H.
通讯作者：
Hanigan, Marie H.
影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME