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 that occur 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 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 ?-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 alo 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 invasion/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 development of agents to target Sin1 as a unique strategy for colon cancer therapeutics.

Public Health Relevance

Colon cancer is the third most commonly diagnosed cancer and the third leading cause of death in both men and women in the United Sates, largely due to the spread of cancer to the liver and lymph nodes. In this proposal, we intend to understand the clinical relevance of an important protein, Sin1, in colon cancer tissues and the role of Sin1 in the spread of the colon tumor. This work will provide an understanding of how Pdcd4, a novel tumor suppressor, modulates Sin1 expression resulting in control of the spread of colon cancer and may lead to a new target for treatment of colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA187839-01A1
Application #
8880738
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2015-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Wang, Q; Zhu, J; Wang, Y-W et al. (2017) Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. Oncogene 36:6225-6234