Abstract 1209: Par-4 as therapy for colon cancer

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Abstract Par-4 (Prostate apoptosis response-4) is a tumor suppressor that induces apoptosis in tumor cells in response to apoptotic stimuli. It has been reported to be reduced in a number of human cancers. We examined the expression levels of Par-4 in human colon cancers and explored the possibility of using Par-4 as a treatment for colon cancer. We found that expression of Par-4 is reduced in human colon cancers 2.65-fold compared to paired normal colon. To assess the role of Par-4 in colon cancer growth, the human colon cancer cell line, HT29, with low native Par-4 expression, was transfected to overexpress Par-4. It has been shown that apoptosis was higher in the transfected cells than in the mock transfected cells. It was also shown that tumors growing in nude mice were smaller when the cells were transfected to overexpress Par-4. Importantly for therapeutic considerations, it has been reported that Par-4 expressing cells can have a bystander effect on tumor cells that are not transfected, also inducing apoptosis in the untransfected cells. We hypothesized that HT29 colon cancer cells producing Par-4 in vivo would secrete Par-4 into the animal system and result in lower tumor volume of tumors created with wild type cells growing distally. Methods: To show proof of concept, nude mice were injected subcutaneously with wild type HT29 cells. Half of the mice were also injected with HT29 cells overexpressing Par-4 in the opposite flank. Mice were treated with 5-fluorouracil to test the sensitivity of tumors to the chemotherapy. Results: At the end of the first week, the wild type tumors in the mice with Par-4 tumors also were 1.8-fold smaller (p=0) than those tumors in mice who received only wild type tumor cell injections. Over the course of three weeks, the wild type tumors growing in mice without Par-4 tumors increased in volume 12-fold more than those wild type tumors growing in mice with Par-4 tumors. In addition, in the event that Par-4 tumors resolved completely (5% of the cases) the wild type tumors in those mice showed increased growth rates. This data suggests that overexpression of Par-4 in tumor cells in vivo not only sensitized those cells to chemotherapy, but had a bystander effect on tumor cells growing distally to the Par-4 overexpressing cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1209.