FOXM1-Induced PRX3 Regulates Stemness and Survival of Colon Cancer Cells via Maintenance of Mitochondrial Function

In-Sung Song, Yu Jeong Jeong, Seung Hun Jeong, Hye Jin Heo, Hyoung Kyu Kim, Ki Beom Bae, Young-Ho Park, Sun Uk Kim, Jin-Man Kim, Nari Kim, Kyung Soo Ko, Byoung Doo Rhee, Jin Han
Gastroenterology 2015, 149 (4): 1006-16.e9

BACKGROUND & AIMS: Reagents designed to target cancer stem cells (CSCs) could reduce tumor growth, recurrence, and metastasis. We investigated the mitochondrial features of CSCs.

METHODS: Colon adenocarcinoma fragments were obtained from 8 patients during surgery at Busan Paik Hospital in Korea. We used immunohistochemistry and quantitative polymerase chain reaction to compare expression of mitochondrial peroxiredoxin 3 (PRX3) in CD133(+)CD44(+) Lgr5(+)cells (CSCs) vs CD133(-)CD44(-)Lgr5(-) colon tumor cells (non-CSCs). Cell survival and expression of mitochondrial-related genes were analyzed in the presence of 5-fluorouracil and/or antimycin A. We used small-interfering and short-hairpin RNAs and an overexpression vector to study PRX3, which functions in the mitochondria. CD133(+) cells with PRX3 knockdown or overexpressing PRX3 were grown as xenograft tumors in immunocompromised mice. Metastasis was studied after injection of tumor cells in spleens of mice. We used chromatin immunoprecipitation and reporter assays to characterize transcriptional regulation of PRX3 by forkhead box proteinĀ 1.

RESULTS: CSCs had a higher mitochondrial membrane potential and increased levels of adenosine triphosphate, Ca(2+), reactive oxygen species, and oxygen consumption than non-CSCs. Levels of PRX3 were increased in colon CSCs compared with non-CSCs. PRX3 knockdown reduced the viability of CSCs, but non non-CSCs, by inducing mitochondrial dysfunction. PRX3 knockdown reduced growth of CSCs as xenograft tumors or metastases in mice. The expression of FOXM1 activated transcription of PRX3 and expression of CD133 in colon CSCs.

CONCLUSIONS: Human colon CSCs have increased mitochondrial function compared with colon tumor cells without stem cell properties. Colon CSCs overexpress the mitochondrial gene PRX3, which is required for maintenance of mitochondrial function and tumorigenesis, and is regulated by forkhead box protein 1, which also regulates expression of CD133 in these cells. These proteins might be therapeutic targets for colorectal cancer.

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