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α-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells

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Abstract

RRR-α-tocopherol ether linked acetic acid analog (α-TEA), is a potential chemotherapeutic agent for ovarian cancer. Pro-death and pro-life signaling pathways were studied to understand the anti-cancer actions of α-TEA on cisplatin-sensitive (A2780S) and -resistant (A2780/cp70R) human ovarian cancer cells. Both cell lines were refractory to Fas; whereas, α-TEA sensitized them to Fas signaling. α-TEA increased levels of Fas message, protein and membrane-associated Fas. Neutralizing antibodies to Fas or Fas L partially blocked α-TEA-induced apoptosis. α-TEA induced prolonged activation of c-Jun N-terminal kinase (JNK) and its substrate c-Jun; Bax conformational change; and cleavage of Bid and caspases-8, -9 and -3. Chemical inhibitors of JNK, and caspases blocked α-TEA-induced apoptosis. α-TEA decreased phosphorylation of protein kinase B (Akt/PKB) and extracellular signal-regulated kinase (ERK1/2), as well as cellular FLICE-like inhibitory protein (c-FLIP) and Survivin protein levels. Knockdown of Akt and ERK activity using phosphoinositide- 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MKK1) inhibitors enhanced α-TEA-induced apoptosis. Over-expression of constitutively active Akt2 and MKK1 blocked α-TEA-induced apoptosis. Collectively, data show α-TEA to be a potent apoptotic inducer of both cisplatin-sensitive and -resistant human ovarian cancer cells via activating death receptor Fas signaling and suppressing anti-apoptotic AKT and ERK targets.

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Authors and Affiliations

  1. School of Biological Sciences/C0900, University of Texas at Austin, Austin, Texas

    Weiping Yu, Hansong Chen & Bob G. Sanders

  2. Division of Nutrition/A2703, University of Texas at Austin, Austin, TX, 78712

    Ming-chieh Shun & Kimberly Kline

  3. Tufts University Boston, MA

    Kristen Anderson

Authors
  1. Weiping Yu
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  2. Ming-chieh Shun
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  3. Kristen Anderson
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  4. Hansong Chen
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  5. Bob G. Sanders
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  6. Kimberly Kline
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Correspondence to Kimberly Kline.

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Yu, W., Shun, Mc., Anderson, K. et al. α-TEA inhibits survival and enhances death pathways in cisplatin sensitive and resistant human ovarian cancer cells. Apoptosis 11, 1813–1823 (2006). https://doi.org/10.1007/s10495-006-9234-5

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  • DOI: https://doi.org/10.1007/s10495-006-9234-5

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