Liao Yong, Yu Dihua, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Adv Exp Med Biol. 2007;608:144-69. doi: 10.1007/978-0-387-74039-3_11.
The adenoviral E1A-mediated sensitization to a variety of anti-cancer drug-induced apoptosis is a well-established phenomenon on different types of cell systems. However, the mechanisms underlying E1A-mediated chemosensitization are still not fully understood. Recent studies demonstrate that E1A-mediated sensitization to drug-induced apoptosis can occur via multiple pathways; some of which depend on the expression of functional p53 and/or p19ARF proteins, while some are not. In human breast cancer cells with Her-2/neu overexpression, which usually are more resistance to anti-cancer drugs than cells without Her-2/ neu overexpression, may be sensitized through E1A-mediated downregulation of Her-2/neu. Alternatively, E1A can induce sensitization to anticancer drugs in cancer cells or normal diploid fibroblast cells through upregulating the expression of caspase proenzymes, or downregulating the activity of a critical survival factor Akt and/or upregulating the activities of a pro-apoptotic kinase p38 and a protein phosphatase PP2A, etc. This review summarizes these progresses and proposes a plausible feed-forward model for E1A-mediated chemosensitization in human breast cancer cells.
腺病毒E1A介导的对多种抗癌药物诱导的细胞凋亡的致敏作用，在不同类型的细胞系统中是一种已被充分证实的现象。然而，E1A介导的化学致敏作用的潜在机制仍未被完全理解。最近的研究表明，E1A介导的对药物诱导的细胞凋亡的致敏作用可通过多种途径发生；其中一些途径依赖于功能性p53和/或p19ARF蛋白的表达，而有些则不依赖。在人Her-2/neu过表达的乳腺癌细胞中，这种细胞通常比无Her-2/neu过表达的细胞对抗癌药物更具抗性，可能通过E1A介导的Her-2/neu下调而致敏。或者，E1A可通过上调半胱天冬酶原酶的表达，或下调关键生存因子Akt的活性和/或上调促凋亡激酶p38和蛋白磷酸酶PP2A的活性等，在癌细胞或正常二倍体成纤维细胞中诱导对抗癌药物的致敏作用。本综述总结了这些进展，并提出了一个关于E1A介导的人乳腺癌细胞化学致敏作用的合理前馈模型。
