Torosyan Yelizaveta, Simakova Olga, Naga Shanmugam, Mezhevaya Katerina, Leighton Ximena, Diaz Juan, Huang Wei, Pollard Harvey, Srivastava Meera
Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Uniformed Services University of Health Sciences School of Medicine, Bethesda, MD 20814, USA.
Int J Cancer. 2009 Dec 1;125(11):2528-39. doi: 10.1002/ijc.24592.
The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/-)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicityin androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased low-molecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC.
膜联蛋白A7（ANXA7）的肿瘤抑制作用先前已通过Anxa7(+/-)小鼠的癌症易感性以及人类癌症中ANXA7的缺失得到证实，尤其是在激素抵抗性前列腺肿瘤中。为了深入了解ANXA7肿瘤抑制的机制，我们进行了一项体外研究，在该研究中，我们将野生型（WT）-ANXA7和显性负性（DN）-ANXA7的作用与传统肿瘤抑制因子p53在具有不同雄激素敏感性的前列腺癌细胞中的作用进行了比较。与p53（在良性前列腺上皮细胞（PrEC）中会在相当程度上导致细胞生长停滞和凋亡）不同，WT-ANXA7在雄激素敏感的LNCaP以及雄激素抵抗的DU145和PC3前列腺癌细胞中表现出显著的细胞毒性，但在PrEC中则没有。在雄激素敏感的LNCaP中，WT-ANXA7降低了低分子量（LMW）雄激素受体（AR）蛋白形式，并维持了较高的视网膜母细胞瘤1（RB1）/磷酸化RB1比率。相比之下，DN-ANXA7（缺乏磷脂酰丝氨酸脂质体聚集特性）增加了LMW-AR形式，并使RB1过度磷酸化，这与DN-ANXA7缺乏细胞毒性一致。根据基于微阵列的 Ingenuity 通路分析，WT-ANXA7在雄激素敏感的LNCaP中的主要作用是上调与RB1结合的转录因子E2F1及其下游促凋亡靶点，如凋亡信号调节激酶1（ASK1）和凋亡相关蛋白2（ASPP2）。这些结果表明，RB依赖性对促凋亡E2F介导转录的抑制发生了逆转。然而，DN-ANXA7增加了RB1/2（但不是E2F1）的表达，并诱导了促进增殖的细胞外信号调节激酶5（ERK5），从而维持了LNCaP中RB依赖性对E2F介导凋亡的抑制。另一方面，在雄激素抵抗细胞中，WT-ANXA7的肿瘤抑制作用涉及磷酸酶和张力蛋白同源物（PTEN）和核因子κB（NFkB）通路。因此，ANXA7恢复了与RB相关的细胞存活控制，克服了雄激素抵抗以及前列腺癌中常见的主要肿瘤抑制因子功能失调状态。2009年由国际抗癌联盟（UICC）发表。
