Redox Regulation of Stem-like Cells Though the CD44v-xCT Axis in Colorectal Cancer: Mechanisms and Therapeutic Implications.
Colorectal cancer (CRC) is a common neoplastic disease and a frequent cause of death. Drug resistance is a major challenge to CRC treatment and stem-like side-population (SP) cells may play a key role in this resistance. Although it has been recognized that cancer stem cells may be affected by redox status, the underlying mechanisms for this effect and the roles of celllular redox adaptation and antioxidant capacity in CRC remain elusive. Our study shows that CRC SP cells are highly dependent on cellular GSH to maintain ROS levels below those of non-SP cells. Exposing CRC cells to H2O2 produced a significant decrease in the percentage of SP cells, which was rescued by adding N-acetylcysteine. Mechanistically, CD44v interacts with and stabilizes xCT and thereby promotes the uptake of cysteine for GSH synthesis and stimulates SP cell enrichment. Additionally, miR-1297 levels were inversely correlated with the expression of xCT; thus, reduced miR-1297 contributes to SP cell enrichment in CRC tumors, which results in tumor aggressiveness and poor clinical outcomes. Importantly, redox modification by PEITC significantly reduces CRC SP cells in vitro and impairs tumors growth in vivo. The combination of 5FU and PEITC led to synergistic cytotoxic effects against CRC cells in vitro and in vivo. Taken together, our data suggest that a GSH-mediated reduction in cellular ROS levels is an essential regulator of CRC SP cells mediated by the CD44v-xCT axis, and disrupting the redox status may eliminate the chemotherapy-resistant CRC SP cells with potentially significant benefits for cancer treatment.
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.; 2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Huai-Qiang
HQ
Ju
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Yun-Xin
YX
Lu
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Dong-Liang
DL
Chen
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Tian
T
Tian
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Hai-Yu
HY
Mo
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Xiao-Li
XL
Wei
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Jian-Wei
JW
Liao
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Feng
F
Wang
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Zhao-Lei
ZL
Zeng
3. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Helene
H
Pelicano
2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mitzi
M
Aguilar
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Wei-Hua
WH
Jia
1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
Rui-Hua
RH
Xu
D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D017879:Isothiocyanates / Q000008:administration & dosage / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome
D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; C058305:phenethyl isothiocyanate; D005978:Glutathione; D005472:Fluorouracil
CD44v-xCT; Colorectal cancer; Redox status; Side population; miR-1297.