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.
Highlights
Oxysterol binding protein (OSBP)-related proteins (ORPs) comprise a mammalian gene family with 12 members [1] implicated in a spectrum of different cellular processes
We found that ORP4L, ORP4M, and ORP4S mRNAs could be detected in human cervical cancer cell lines HeLa, C33A and CaSki (Figure 1A)
Our observations showed that ORP4L knockdown significantly reduced nuclear factor of activated T cells (NFAT) activity in C33A cells, which could be partly rescued by the Ca2+ ionophore ionomycin (Figure 3A)
Summary
Oxysterol binding protein (OSBP)-related proteins (ORPs) comprise a mammalian gene family with 12 members [1] implicated in a spectrum of different cellular processes. The NFAT family contains five members, including four calciumresponsive isoforms named NFAT1 [18, 19], NFAT2 [20], NFAT3 and NFAT4 [21, 22], and a tonicity-responsive enhancer-binding protein (TonEBP, known as NFAT5) [23]. They are usually activated by increased intracellular Ca2+ levels and subsequently translocated into the nucleus. The NFAT isoforms are constitutively activated and overexpressed in several cancer types wherein they transactivate downstream targets that play important roles in cancer cell growth, survival, invasion and angiogenesis [25]
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