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Description

Colon cancer is the third most fatal cancer in both men and women in the United States. For more than 90% of patients who develop hepatic metastases, the disease is fatal within 5 years: often within 1-2 years. Inactivation of tumor suppressor genes is one type of somatic genetic changes in colon cancer. Understanding the function and action mechanism of tumor suppressors in colon cancer metastasis will benefit the design of new therapeutic drugs to reduce the mortality rate of metastatic colon cancer. Programmed cell death 4 (Pdcd4), a novel tumor suppressor, is frequently down-regulated in cancerous colon tissues compared to adjacent normal tissues. Indeed, knockdown of Pdcd4 expression in the colon tumor cells promotes invasion in cultured cells and metastasis in nude mice. Conversely, over-expression of Pdcd4 inhibits colon tumor cell invasion and intravasation. Promotion of tumor invasion by Pdcd4 knockdown is believed to elevate Snail expression and thereby down-regulate E-cadherin and activate â-catenin and AP-1 dependent transcription. In addition, Pdcd4 has been demonstrated to inhibit protein translation through its ability to bind with translation initiation factor 4A (eIF4A). Pdcd4 has also been shown to inhibit activation of Akt (also known as protein kinase B), a kinase frequently activated in human colon cancer. Preliminary studies showed that knockdown of Akt suppresses colon tumor cell invasion caused by Pdcd4 knockdown, suggesting that Pdcd4 controls colon tumor invasion/metastasis via regulation of Akt activation. A key finding was that over-expression of Pdcd4 inhibits the level of Sin1 (stress-activated-protein kinase-interacting protein 1), whereas knockdown of Pdcd4 elevates Sin1. In addition, knockdown of Pdcd4 increased Sin1 translation. Since Sin1 is a critical component of mammalian target of rapamycin complex 2 (mTORC2), which controls Akt activation, these promising findings suggest a mechanism by which Pdcd4 regulates Akt activation through the control of Sin1 translation. However, the clinical importance of Sin1 expression in colon cancer progression, and the role of Sin1 in colon tumor cell metastasis are unknown. Since Pdcd4 suppresses colon tumor invasion/metastasis and inhibits Sin1 expression, the hypothesis is that Pdcd4 suppresses colon tumor cell invasion/metastasis through inhibition of Sin1 translation. To test this hypothesis, two specific aims are proposed. Aim 1: determine whether Sin1 expression correlates with colon cancer progression. Aim 2: determine whether suppression of Sin1 translation by Pdcd4 leads to inhibition of Akt activation thereby impeding invasion/metastasis. Accomplishment of the proposed study will establish the clinical significance of Sin1 expression in colon cancer progression and the promoter role of Sin1 in colon tumor invasion/metastasis. The proposed work is highly innovative and of significant impact given the translational value in providing a solid rationale for agents development to target Sin1 for a unique strategy for colon cancer therapeutics.
StatusFinished
Effective start/end date4/1/159/30/17

Funding

  • National Cancer Institute: $150,438.00

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