Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-β.
Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-β.
复制标题
DOI：
10.1016/j.molonc.2014.10.008
复制
发表时间：
2015-02
影响因子：
6.6
通讯作者：
Tepe JJ
中科院分区：
文献类型：
--
作者：
Basson MD;Zeng B;Downey C;Sirivelu MP;Tepe JJ
大肿瘤表现出高间质压力，该压力因对抗基质的限制而生长而升高。这种压力可以通过机械敏感离子通道刺激肿瘤增殖。我们研究了 0-80 mm Hg 细胞外压增加 24 小时对 SW620、Caco-2 和 CT-26 结肠增殖的影响； MCF-7 乳房；以及 MLL 和 PC3 前列腺癌细胞，并用特异性抑制剂和 siRNA 描述了其在 SW620 细胞中的机制。最后，我们比较了人类肿瘤高压中心和低压外周的 NF-kB、磷酸-IkB 和细胞周期蛋白 D1 免疫反应性。压力刺激所有细胞的增殖。压力驱动的 SW620 增殖需要钙通过 T 型 Ca2+ 通道 Cav3.3 流入，刺激 PKC-β 调用 IKK-IkB-NF-kB 途径以增加增殖和 S 期分数。 28个大型人类结肠、肺、头颈肿瘤中心的有丝分裂指数和NF-kB、磷酸-IkB和细胞周期蛋白D1的免疫反应性超过肿瘤外围。细胞外压力通过 Cav3.3 增加 [Ca2+]i，驱动 PKC-β-IKK-IkB-NF-kB 通路，刺激癌细胞增殖。大型僵硬肿瘤的快速增殖可能会增加瘤内压力，激活该途径以刺激反馈循环中的进一步增殖，从而增强肿瘤生长。靶向该途径可能会抑制大型不可切除肿瘤的增殖。
Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0–80 mm Hg increased extracellular pressure for 24 hours on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca2+ channel Cav3.3, which stimulated PKC-β to invoke the IKK-IkB-NF-kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca2+]i via Cav3.3, driving a PKC-β-IKK-IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors.
登录
查看更多内容
影响因子：
5.5
作者：
Craig, David H.;Gayer, Christopher P.;Basson, Marc D.
通讯作者：
Basson, Marc D.
影响因子：
3.9
作者：
Basson, MD;Hong, F
通讯作者：
Hong, F
DOI：
10.1124/jpet.103.060814
发表时间：
2004-04-01
影响因子：
3.5
作者：
Huang, LP;Keyser, BM;Li, M
通讯作者：
Li, M
影响因子：
8
作者：
Downey, C.;Craig, D. H.;Basson, M. D.
通讯作者：
Basson, M. D.
影响因子：
3.4
作者：
Calabrese, B;Tabarean, IV;Morris, CE
通讯作者：
Morris, CE