Oncotarget

Research Papers:

RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer

Huang Ruihua, Zhang Mengyi, Zhao Chong, Qiu Meng, Ma Xin, Tang Qiulin, Bi Feng and Liu Ming _

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Oncotarget. 2016; 7:87136-87146. https://doi.org/10.18632/oncotarget.13548

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Abstract

Huang Ruihua1, Zhang Mengyi1, Zhao Chong2, Qiu Meng1, Ma Xin1, Tang Qiulin1, Bi Feng1, Liu Ming1

1Department of Medical Oncology/Laboratory of Signal Transduction and Molecular Targeted Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

2Department of Radiotherapy, The Tumor Hospital of Chengdu/The Seventh Peoples’s Hospital of Chengdu, Chengdu, Sichuan Province, China

Correspondence to:

Liu Ming, email: [email protected]

Keywords: irinotecan, RhoA, colorectal cancer, chemoresistance

Received: March 09, 2016     Accepted: November 08, 2016     Published: November 24, 2016

ABSTRACT

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. While surgery remains the mainstay of treatment in early stage CRC, chemotherapy is usually given to prolong the overall survival and improve the quality of life for metastatic colorectal cancer (mCRC). But drug resistance is one of the major hurdles of mCRC treatment, and the underlying mechanisms are still largely unknown. In this study, we show that, compared with parental cells, RhoA is up-regulated in irinotecan (CPT-11)-resistant CRC cells. Furthermore, inhibition of RhoA in drug resistant cells, at least partially, rescues the resistance against irinotecan and increases the sensitivity to other chemotherapeutic drug by inhibiting expression of MDR1, MRP1and GSTP1, promotes apoptosis by suppressing the expression of BCL-XL and Bcl-2 and increasing Bax expression, and significantly decreases side population cells. Our results suggest that, in addition to survival, proliferation, migration, adhesion, cell cycle and gene transcription, RhoA is also involved in chemoresistance by regulating the expression of membrane transporter and apoptosis protein in colorectal cancer. They raise an interesting possibility that the expression of RhoA may indicate a poor prognosis due to the high probability to therapy resistance and, on the other hand, inhibition of RhoA activity and function may overcome chemoresistance and improve the effectiveness of clinical treatment of CRC.


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