Ciocca Daniel R, Rozados Viviana R, Cuello Carrión F Darío, Gervasoni Silvia I, Matar Pablo, Scharovsky O Graciela
Institute of Experimental Medicine and Biology, Regional Center for Scientific and Technological Research, CONICET, c.c. 855, (5500), Mendoza, Argentina.
Cell Stress Chaperones. 2003 Spring;8(1):26-36. doi: 10.1379/1466-1268(2003)8<26:hahirt>2.0.co;2.
Heat shock protein 27 (Hsp27) and Hsp70 have been involved in resistance to anticancer drugs in human breast cancer cells growing in vitro and in vivo. In this study, we examined the expression of Hsp25 (the rodent homologue to human Hsp27) and Hsp70 in 3 different rodent tumors (a mouse breast carcinoma, a rat sarcoma, and a rat lymphoma maintained by subcutaneous passages) treated in vivo with doxorubicin (DOX) and lovastatin (LOV). All tumors showed massive cell death under control untreated conditions, and this massive death increased after cytotoxic drug administration. In this study, we show that this death was due to classic apoptosis. The tumors also showed isolated apoptotic cells between viable tumor cells, and this occurred more significantly in the lymphoma. The tumor type that was more resistant to cell death was the sarcoma, and this was found in sarcomas growing both under control conditions and after cytotoxic drug administration. Moreover, sarcomas showed the highest expression levels of Hsp25 in the viable tumor cells growing under untreated conditions, and these levels increased after DOX and LOV administration. After drug treatment, only sarcoma tumor cells showed a significant increase in Hsp70. In other words, sarcomas were the tumors with lower cell death, displayed a competent Hsp70 and Hsp25 response with nuclear translocation, and had the highest levels of Hsp25. In sarcomas, Hsp25 and Hsp70 were found in viable tumor cells located around the blood vessels, and these areas showed the most resistant tumor cell phenotype after chemotherapy. In addition, Hsp25 expression was found in endothelial cells as unique feature revealed only in lymphomas. In conclusion, our study shows that each tumor type has unique features regarding the expression of Hsp25 and Hsp70 and that these proteins seem to be implicated in drug resistance mainly in sarcomas, making these model systems important to perform more mechanistic studies on the role of Hsps in resistance to certain cytotoxic drugs.
热休克蛋白27（Hsp27）和Hsp70参与了体外和体内生长的人乳腺癌细胞对抗癌药物的耐药性。在本研究中，我们检测了用阿霉素（DOX）和洛伐他汀（LOV）进行体内治疗的3种不同啮齿动物肿瘤（一种小鼠乳腺癌、一种大鼠肉瘤和一种通过皮下传代维持的大鼠淋巴瘤）中Hsp25（人类Hsp27的啮齿动物同源物）和Hsp70的表达。所有肿瘤在未治疗的对照条件下均显示大量细胞死亡，细胞毒性药物给药后这种大量死亡增加。在本研究中，我们表明这种死亡是由于经典凋亡。肿瘤在存活的肿瘤细胞之间也显示出孤立的凋亡细胞，这在淋巴瘤中更为明显。对细胞死亡更具抗性的肿瘤类型是肉瘤，这在对照条件下生长以及细胞毒性药物给药后的肉瘤中均有发现。此外，肉瘤在未治疗条件下生长的存活肿瘤细胞中显示出最高水平的Hsp25表达，DOX和LOV给药后这些水平升高。药物治疗后，只有肉瘤肿瘤细胞显示Hsp70显著增加。换句话说，肉瘤是细胞死亡较低的肿瘤，表现出具有核转位的有效Hsp70和Hsp25反应，并且具有最高水平的Hsp25。在肉瘤中，Hsp25和Hsp70存在于血管周围的存活肿瘤细胞中，这些区域在化疗后显示出最具抗性的肿瘤细胞表型。此外，Hsp25表达在内皮细胞中被发现，这是仅在淋巴瘤中揭示的独特特征。总之，我们的研究表明每种肿瘤类型在Hsp25和Hsp70的表达方面具有独特特征，并且这些蛋白质似乎主要在肉瘤中与耐药性有关，使得这些模型系统对于进行关于热休克蛋白在对某些细胞毒性药物的耐药性中的作用的更多机制研究很重要。
