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CPNE1 Enhances Colorectal Cancer Cell Growth, Glycolysis, and Drug Resistance Through Regulating the AKT-GLUT1/HK2 Pathway

Authors Wang Y, Pan S, He X, Wang Y, Huang H, Chen J, Zhang Y, Zhang Z, Qin X

Received 29 September 2020

Accepted for publication 4 December 2020

Published 27 January 2021 Volume 2021:14 Pages 699—710

DOI https://doi.org/10.2147/OTT.S284211

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Arseniy Yuzhalin


Yuexia Wang,1,* Shengli Pan,2,* Xinhong He,3 Ying Wang,3 Haozhe Huang,3 Junxiang Chen,3 Yuhao Zhang,2 Zhijin Zhang,2 Xianju Qin2

1Department of General Surgery, Shanghai Eighth People’s Hospital, Jiangsu University, Shanghai, People’s Republic of China; 2Department of General Surgery, Shanghai Eighth People’s Hospital, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Shengli Pan; Xianju Qin
Department of General Surgery, Shanghai Eighth People’s Hospital, Caobao Road No. 8, Shanghai 200232, People’s Republic of China
Tel +86-21-34284588
Email panshengli171107@163.com; qinxj@hotmail.com

Introduction: Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. Copines-1 (CPNE1) has been shown to be overexpressed in various cancers; however, the role of CPNE1 in CRC remains unknown. Therefore, it is of great importance to elucidate the role of CPNE1 in CRC and its underlying mechanism of action.
Methods: CPNE1 expression in CRC tissues was measured by quantitative real-time PCR and immunohistochemical (IHC) staining. CPNE1 was knocked down (KD) or overexpressed using small inferring RNAs or lentiviral transduction in CRC cells. The proliferation, apoptosis, glycolysis, and mitochondrial respiration of CRC cells were assessed by cell counting kit-8, flow cytometry, and Xfe24 extracellular flux analyzer assays, respectively. The role of CPNE1 in tumor growth and chemoresistance was further confirmed in xenograft and patient-derived tumor xenograft models, respectively.
Results: CPNE1 mRNA and protein were upregulated in CRC tissues. CPNE1 promoted proliferation, inhibited apoptosis, increased mitochondrial respiration, enhanced aerobic glycolysis by activating AKT signaling, upregulated glucose transporter 1 (GLUT1) and hexokinase 2 (HK2), and downregulated the production of cleaved Caspase-3 (c-Caspase 3). CPNE1 also contributed to chemoresistance in CRC cells. CPNE1 KD inhibited tumor growth and increased the sensitivity of tumors to oxaliplatin in vivo.
Conclusion: CPNE1 promotes CRC progression by activating the AKT-GLUT1/HK2 cascade and enhances chemoresistance.

Keywords: copines-1, colorectal cancer, aerobic glycolysis, mitochondrial respiration

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