Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer mortality and 5-Fluorouracil (5-FU) is the most common chemotherapy agent of CRC. A high level of X-ray repair cross complementing group 1 (XRCC1) in cancer cells has been associated with the drug resistance occurrence. Moreover, the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been indicated to regulate the cancer cell survival. Thus, this study was aimed to examine whether XRCC1 plays a role in the 5-FU/AMPK agonist (AICAR)-induced cytotoxic effect on CRC and the underlying mechanisms. Human HCT-116 colorectal cells were used in this study. It was shown that 5-FU increases the XRCC1 expression in HCT-116 cells and then affects the cell survival through CXCR4/Akt signaling. Moreover, 5-FU combined with AICAR further result in more survival inhibition in HCT-116 cells, accompanied with reduced CXCR4/Akt signaling activity and XRCC1 expression. These results elucidate the role and mechanism of XRCC1 in the drug resistance of HCT-116 cells to 5-FU. We also demonstrate the synergistic inhibitory effect of AMPK on 5-FU-inhibited HCT-116 cell survival under the 5-FU and AICAR co-treatment. Thus, our findings may provide a new notion for the future drug regimen incorporating 5-FU and AMPK agonists for the CRC treatment.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women [1]
Downregulation of X-ray repair cross complementing group 1 (XRCC1) expression potentiated 5-FU-induced cytotoxicity and enhanced its chemosensitizing effect by suppressing CXCR4 and Akt signaling in CRC cells
The results of this study demonstrate that 5-FU treatment induced XRCC1 mRNA and protein expression in human CRC cells
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women [1]. PPII33KK//AAkktt SSiiggnnaalliinngg RReegguullaatteess tthhee XXRRCCCC11 EExxpprreessssiioonn aanndd CCeellll CCyyttoottooxxiicciittyy ooff HHCCTT--111166 CCeellllss uunnddeerr 55--FFUU SSttiimmuullaattiioonn. Too eevvaalluuaate tthhee rroollee ooff CCXXCCRR44 iinn 55--FFUU--iinndduucceedd AAkktt pphhoosspphhoorryyllaattiioonnaannddXXRRCCCC11eexxpprreessssiioonn,,HHCCTT--111166cceellllsswweerreettrraannssffeecctteeddwwiitthh CXCR4--ssppeecciifificcssiiRRNNAA aanndd ffoolllloowweedd bbyy ssttiimmuullaattiioonn wwiitthh 55--FFUU. Downregulation of XRCC1 expression potentiated 5-FU-induced cytotoxicity and enhanced its chemosensitizing effect by suppressing CXCR4 and Akt signaling in CRC cells. Inhibition of XRCC1 expression played a significant role in enhancing the 5-FU-induced cytotoxic effect in CRC cells. The results of this study demonstrate that 5-FU treatment induced XRCC1 mRNA and protein expression in human CRC cells. Inhibition of Akt activation, and CXCR4 and XRCC1 expression by AICAR, enhanced the 5-FU-induced cytotoxicity in CRC cells. The in vivo animal studies are needed to confirm these in vivo studies
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