title: Oxysterol-binding protein-related protein 4L promotes cell proliferation by sustaining intracellular Ca2+ homeostasis in cervical carcinoma cell lines.
abstract: 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.
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Ji-Wei
authors: JW
authors: Li
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Yan-Lin
authors: YL
authors: Xiao
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Chao-Feng
authors: CF
authors: Lai
authors: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China.
authors: Ning
authors: N
authors: Lou
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Hong-Ling
authors: HL
authors: Ma
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Bi-Ying
authors: BY
authors: Zhu
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Wen-Bin
authors: WB
authors: Zhong
authors: Department of Biotechnology, Jinan University, Guangzhou, 510632, China.|The Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou, 510632, China.
authors: Dao-Guang
authors: DG
authors: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D000072376:Oxysterols / Q000378:metabolism; D020033:Protein Isoforms; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000098825:Oxysterol Binding Proteins
chemical_list: D014408:Biomarkers, Tumor; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050778:NFATC Transcription Factors; D000072376:Oxysterols; D020033:Protein Isoforms; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D002118:Calcium
keywords: Ca2+ homeostasis; IP3R1; NFAT; ORP4L; proliferation