New insights into store-independent Ca²⁺ entry: secretory pathway calcium ATPase 2 in normal physiology and cancer

Abstract

Blocking an enzyme that helps bring calcium into cells could be a promising strategy for therapeutic intervention in oral cancers. In a review article, Rajini Rao from the Johns Hopkins University School of Medicine, USA, and her former graduate student Ming-Ye Feng, now at Sichuan University, China, and Stanford University, USA, discuss how a calcium-pumping enzyme known as secretory pathway Ca²⁺-ATPase 2 (SPCA2) is often upregulated in cancer cells compared to their non-malignant counterparts. Salivary glands express this protein during normal tissue development. When SPCA2 is overexpressed, however, calcium ions rush into the cells, leading to increased proliferation and other characteristics consistent with tumorigenic growth. Therefore, SPCA2 or the calcium channels it interacts with could be a useful new drug target in patients with oral cancer.

Keywords

Ca²⁺ signaling / human cancers / store-independent Ca²⁺ entry / store-operated Ca²⁺ entry

References

[1] Strehler EE, Zacharias DA. Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol Rev, 2001, 81(1): 21-50.

[2] East JM. Sarco(endo)plasmic reticulum calcium pumps: recent advances in our understanding of structure/function and biology (review). Mol Membr Biol, 2000, 17(4): 189-200.

[3] Sorin A, Rosas G, Rao R. PMR1, a Ca²⁺-ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. J Biol Chem, 1997, 272(15): 9895-9901.

[4] Durr G, Strayle J, Plemper R. The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca²⁺ and Mn²⁺ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Mol Biol Cell, 1998, 9(5): 1149-1162.

[5] Vanoevelen J, Dode L, Van Baelen K. The secretory pathway Ca²⁺/Mn²⁺-ATPase 2 is a Golgi-localized pump with high affinity for Ca²⁺ ions. J Biol Chem, 2005, 280(24): 22800-22808.

[6] Xiang M, Mohamalawari D, Rao R. A novel isoform of the secretory pathway Ca²⁺,Mn²⁺-ATPase, hSPCA2, has unusual properties and is expressed in the brain. J Biol Chem, 2005, 280(12): 11608-11614.

[7] Okunade GW, Miller ML, Azhar M. Loss of the Atp2c1 secretory pathway Ca²⁺-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. J Biol Chem, 2007, 282(36): 26517-26527.

[8] Feng M, Grice DM, Faddy HM. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell, 2010, 143(1): 84-98.

[9] Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev, 2005, 85(2): 757-810.

[10] Cahalan MD, Zhang SL, Yeromin AV. Molecular basis of the CRAC channel. Cell Calcium, 2007, 42(2): 133-144.

[11] Gwack Y, Feske S, Srikanth S. Signalling to transcription: store-operated Ca²⁺ entry and NFAT activation in lymphocytes. Cell Calcium, 2007, 42(2): 145-156.

[12] Lewis RS. The molecular choreography of a store-operated calcium channel. Nature, 2007, 446(7133): 284-287.

[13] Vig M, Kinet JP. The long and arduous road to CRAC. Cell Calcium, 2007, 42(2): 157-162.

[14] Feske S, Gwack Y, Prakriya M. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature, 2006, 441(7090): 179-185.

[15] Prakriya M, Feske S, Gwack Y. Orai1 is an essential pore subunit of the CRAC channel. Nature, 2006, 443(7108): 230-233.

[16] Vig M, Peinelt C, Beck A. CRACM1 is a plasma membrane protein essential for store-operated Ca²⁺ entry. Science, 2006, 312(5777): 1220-1223.

[17] Garside VC, Kowalik AS, Johnson CL. MIST1 regulates the pancreatic acinar cell expression of Atp2c2, the gene encoding secretory pathway calcium ATPase 2. Exp Cell Res, 2010, 316(17): 2859-2870.

[18] Lee WJ, Monteith GR, Roberts-Thomson SJ. Calcium transport and signaling in the mammary gland: targets for breast cancer. Biochim Biophys Acta, 2006, 1765(2): 235-255.

[19] Faddy HM, Smart CE, Xu R. Localization of plasma membrane and secretory calcium pumps in the mammary gland. Biochem Biophys Res Commun, 2008, 369(3): 977-981.

[20] Anantamongkol U, Takemura H, Suthiphongchai T. Regulation of Ca²⁺ mobilization by prolactin in mammary gland cells: possible role of secretory pathway Ca²⁺-ATPase type 2. Biochem Biophys Res Commun, 2007, 352(2): 537-542.

[21] Jiang L, Zeng X, Yang H. Oral cancer overexpressed 1 (ORAOV1): a regulator for the cell growth and tumor angiogenesis in oral squamous cell carcinoma. Int J Cancer, 2008, 123(8): 1779-1786.

[22] Liu LH, Boivin GP, Prasad V. Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca²⁺-ATPase isoform 2 Ca²⁺ pump. J Biol Chem, 2001, 276(29): 26737-26740.

[23] Endo Y, Uzawa K, Mochida Y. Sarcoendoplasmic reticulum Ca²⁺ ATPase type 2 downregulated in human oral squamous cell carcinoma. Int J Cancer, 2004, 110(2): 225-231.

[24] Saito K, Uzawa K, Endo Y. Plasma membrane Ca²⁺ ATPase isoform 1 down-regulated in human oral cancer. Oncol Rep, 2006, 15(1): 49-55.

[25] Huang JK, Huang CJ, Chen WC. Independent [Ca²⁺]_i increases and cell proliferation induced by the carcinogen safrole in human oral cancer cells. Naunyn Schmiedebergs Arch Pharmacol, 2005, 372(1): 88-94.