Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines
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Ji-Wei Li1,2,*, Yan-Lin Xiao1,2,*, Chao-Feng Lai1,2,*, Ning Lou3, Hong-Ling Ma1,2, Bi-Ying Zhu1,2, Wen-Bin Zhong1,2, Dao-Guang Yan1,2
1Department of Biotechnology, Jinan University, Guangzhou, 510632, China
2The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China
3State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
*These authors have contributed equally to this work
Dao-Guang Yan, email: firstname.lastname@example.org
Wen-Bin Zhong, email: email@example.com
Keywords: ORP4L, Ca2+ homeostasis, NFAT, IP3R1, proliferation
Received: February 22, 2016 Accepted: August 09, 2016 Published: August 29, 2016
Oxsterol binding protein-related protein 4 (ORP4) is essential for cell proliferation, but the underlying mechanism is unclear. ORP4 is expressed as three variants, ORP4L, ORP4M and ORP4S. Here, we reported that silencing of ORP4L with specific small interfering RNA (siRNA) inhibited the proliferation of human cervical cancer cell lines C33A, HeLa and CaSki, the reverse effect being observed in ORP4L overexpressing cells. For molecular insight, we found that ORP4L maintained intracellular Ca2+ homeostasis. Through this mechanism, ORP4L activated nuclear factor of activated T cells (NFAT) activity and thus promoted expression of a gene cluster which supported cell proliferation. Of note, ORP4L sustained inositol-1,4,5-trisphosphate receptor 1 (IP3R1) expression at both mRNA and protein levels via Ca2+-dependent NFAT3 activation, which offered a mechanic explanation for the role of ORP4L intracellular Ca2+ homeostasis. Furthermore, ORP4L knockdown markedly inhibited tumor growth in a C33A cell xenograft mouse model. To conclude, our results reveal that ORP4L promotes cell proliferation through maintaining intracellular Ca2+ homeostasis.
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