PTHrP expression in human MDA-MB-231 breast cancer cells is critical for tumor growth and survival and osteoblast inhibition.
PTHrP expression in human MDA-MB-231 breast cancer cells is critical for tumor growth and survival and osteoblast inhibition.
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DOI：
10.7150/ijbs.7039
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发表时间：
2013
影响因子：
9.2
通讯作者：
Xiao G
中科院分区：
文献类型：
--
作者：
Zheng L;Zhu K;Jiao H;Zhao Z;Zhang L;Liu M;Deng W;Chen D;Yao Z;Xiao G
本研究探讨了人乳腺癌细胞来源的甲状旁腺激素相关蛋白(PTHrP)对肿瘤生长和成骨细胞的抑制作用。结果表明，下调乳腺癌细胞中PTHrP的表达可显著抑制裸鼠皮下肿瘤的形成。PTHrP基因敲除显著降低了细胞周期蛋白D1和A1的水平，使细胞周期停滞于G1期。PTHrP基因敲除导致Caspase8的裂解，诱导肿瘤细胞的凋亡。有趣的是，下调PTHrP可增加Beclin1和Lc3-II的水平，并促进自噬小体的形成。在体内外，下调PTHrP的表达显著降低了乳腺癌细胞抑制成骨细胞分化和骨形成的能力。最后，我们发现PTHrP通过自分泌机制激活了其在MDA-MB-231细胞中的表达。总之，这些研究表明，靶向肿瘤细胞中PTHrP的表达可能是乳腺癌，特别是那些有骨转移的乳腺癌的潜在治疗策略。
This study examined the effects of parathyroid hormone-related protein (PTHrP) derived from human MDA-MB-231 breast cancer cells on the tumor growth and osteoblast inhibition. Results revealed that knocking down PTHrP expression in the breast cancer cells strikingly inhibited the formation of subcutaneous tumors in nude mice. PTHrP knockdown dramatically decreased the levels of cyclins D1 and A1 proteins and arrested the cell cycle progression at the G1 stage. PTHrP knockdown led to the cleavage of Caspase 8 and induced apoptosis of the tumor cells. Interestingly, knocking down PTHrP increased the levels of Beclin1 and LC3-II and promoted the formation of autophagosomes. Knocking down PTHrP expression significantly reduced the abilities of the breast cancer cells to inhibit osteoblast differentiation and bone formation in vitro and in vivo. Finally, we found that PTHrP activated its own expression through an autocrine mechanism in MDA-MB-231 cells. Collectively, these studies suggest that targeting PTHrP expression in the tumor cells could be a potential therapeutic strategy for breast cancers, especially those with skeletal metastases.
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