WISP-2/CCN5 is involved as a novel signaling intermediate in phorbol ester-protein kinase Calpha-mediated breast tumor cell proliferation.
WISP-2/CCN5 is involved as a novel signaling intermediate in phorbol ester-protein kinase Calpha-mediated breast tumor cell proliferation.
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WISP-2/CCN5 作为一种新型信号中间体参与佛波酯蛋白激酶 Cα 介导的乳腺肿瘤细胞增殖。
DOI：
10.1021/bi060888p
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发表时间：
2006
期刊：
影响因子：
2.9
通讯作者：
Banerjee,SushantaK
中科院分区：
文献类型：
--
作者：
Sengupta,Krishanu;Banerjee,Snigdha;Dhar,Kakali;Saxena,NeelaK;Mehta,Smita;Campbell,DonaldR;Banerjee,SushantaK
PMA和活性磷酯刺激各种肿瘤细胞的增殖，包括er阳性的人乳腺肿瘤细胞系。然而，pma诱导的乳腺肿瘤细胞有丝分裂作用的具体信号通路尚未完全阐明。在本研究中，我们探讨了PMA对乳腺肿瘤细胞有丝分裂影响的相关机制。急性暴露（即在2 ~ 6小时内）于PMA （50 nM）后，观察到WISP-2/CCN5阳性乳腺肿瘤细胞系，包括MCF-7， ZR-75-1和SKBR-3细胞的有丝分裂作用，并且诱导WISP-2/CCN5 mRNA表达与观察到的有丝分裂增殖平行。在转染ER-α或未转染ER-α的WISP-2/CCN5阴性MDA-MB-231乳腺肿瘤细胞或人乳腺上皮细胞中未检测到这种效应。短发夹RNA （short hairpin RNA, shRNA）介导的MCF-7细胞中WISP-2/CCN5信号通路的抑制干扰了PMA的有丝分裂作用。此外，PMA上调WISP-2/CCN5不依赖于ER，而是通过复杂的PKCα-MAPK/ERK和SAPK/JNK信号通路介导，从而导致MCF-7乳腺肿瘤细胞的生长刺激。这一系列实验首次证明，WISP-2/CCN5是一种新的信号分子，通过pkc α依赖的多分子信号转导途径，关键参与PMA对无创、WISP-2/CCN5阳性乳腺肿瘤细胞的有丝分裂作用。
PMA and active phorbol esters stimulate the proliferation of various tumor cells, including ER-positive human breast tumor cell lines. However, the specific signaling pathways involved in the PMA-induced mitogenic effect on breast tumor cells have not been fully elucidated. In the present study, we explored the mechanisms associated with the mitogenic influence of PMA on breast tumor cells. Following an acute exposure (i.e., within 2 to 6 h) to PMA (50 nM), a mitogenic effect was observed on WISP-2/CCN5-positive breast tumor cell lines, including MCF-7, ZR-75-1 and SKBR-3 cells, and induction of WISP-2/CCN5 mRNA expression paralleled the observed mitogenic proliferation. This effect was undetected in WISP-2/CCN5 negative MDA-MB-231 breast tumor cells or human mammary epithelial cells with or without ER-α transfection. The mitogenic effect of PMA was perturbed by short hairpin RNA (shRNA)-mediated inhibition of WISP-2/CCN5 signaling in MCF-7 cells. Moreover, the upregulation of WISP-2/CCN5 by PMA is not ER dependent but is instead mediated through a complex PKCα-MAPK/ERK and SAPK/JNK signaling pathway, which leads to growth stimulation of MCF-7 breast tumor cells. These series of experiments provide the first evidence that WISP-2/CCN5 is a novel signaling molecule that critically participates in the mitogenic action of PMA on noninvasive, WISP-2/CCN5-positive breast tumor cells through PKCα-dependent, multiple molecular signal transduction pathways.