Recent studies in secretory pathway calcium ATPases （SPCA） revealed novel functions of SPCA2 in interacting with store-operated Ca2＋ channel Oral I and inducing Ca2＋ influx at the cell surface. Importantly, SPCA2-...Recent studies in secretory pathway calcium ATPases （SPCA） revealed novel functions of SPCA2 in interacting with store-operated Ca2＋ channel Oral I and inducing Ca2＋ influx at the cell surface. Importantly, SPCA2-mediated Ca2＋ signaling is uncoupled from its conventional role of Ca2＋-ATPase and independent of store-operated Ca2＋ signaling pathway. SPCA2-induced store-independent Ca2＋ entry （SICE） plays essential roles in many important physiological processes, while unbalanced SICE leads to enhanced cell proliferation and tumorigenesis. Finally, we have summarized the clinical implication of SICE in oral cancer prognosis and treatment. Inhibition of SICE may be a new target for the development of cancer therapeutics.展开更多
Store-operated Ca2＋ channels （SOCs） are plasma membrane Ca2＋ permeable channels activated by depletion of intracellular Ca2＋ store. Ca2＋ entry through SOCs is known as store-operated Ca2＋ entry （SOCE）, which ...Store-operated Ca2＋ channels （SOCs） are plasma membrane Ca2＋ permeable channels activated by depletion of intracellular Ca2＋ store. Ca2＋ entry through SOCs is known as store-operated Ca2＋ entry （SOCE）, which plays an important role in the functional regulation of airway smooth muscle cells （ASMCs）. Protein kinase C （PKC） has been shown to have an activating or inhibiting effect on SOCE, depending on cell types and PKC isoforms that are involved. In ASMCs, the effect of PKC on SOCE has not been elucidated so far. In this study, the role of PKC in the activation of SOCE in rat ASMCs was examined by using Ca2＋ fluorescence imaging technique. The results showed that acute application of PKC activators PMA and PDBu did not affect SOCE induced by the sarcoplasmic reticulum Ca2＋-ATPase （SERCA） inhibitor thapsigargin. The non-selective PKC inhibitor chelerythrine significantly inhibited thapsigargin- and bradykinin-induced SOCE. RT-PCR assay identified PKCα, δ and ε isoforms in rat ASMCs. PKCα-selective inhibitor G6976 and PKCε-inhibiting peptide Epsilon-V1-2 had no effect on SOCE; by contrast, PKCδ-selective inhibitor rottlerin attenuated SOCE dramatically, suggesting that PKCδ was the major PKC isoform involved in the activation of SOCE in ASMCs. Moreover, PKC down-regulation by extended exposure to high doses of PMA or PDBu also reduced SOCE, confirming the essential role of PKC in the activation of SOCE in ASMCs. In addition, PKC down-regulation did not influence the expression of stromal interaction molecule 1 （STIM1） and Orai1, two elementary molecules in the regulation and activation of SOCs. These results identified PKCδ as an essential PKC isoform involved in the activation of SOCE, and confirmed that PKC regulates the function of ASMCs in a SOCE-dependent manner.展开更多
The intracellular calcium ions(Ca^(2+)) act as second messenger to regulate gene transcription,cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca^(2+)homeostasis is...The intracellular calcium ions(Ca^(2+)) act as second messenger to regulate gene transcription,cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca^(2+)homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis,progression and metastasis. Targeting derailed Ca^(2+)signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca^(2+)channels, transporters and Ca^(2+)-ATPases,which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca^(2+)channels/transporters or Ca^(2+)-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for researchinto the understanding of cellular mechanisms underlying the regulation of Ca^(2+)signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca^(2+)channels or transporters.展开更多
基金supported by grant GM62142 from the National Institution of Health to Rajini RaoAmerican Heart Association Pre-doctoral Fellowship 0815058E to Ming-Ye Fengsupported by Open Fund of State Key Laboratory of Oral Diseases, Sichuan University
文摘Recent studies in secretory pathway calcium ATPases （SPCA） revealed novel functions of SPCA2 in interacting with store-operated Ca2＋ channel Oral I and inducing Ca2＋ influx at the cell surface. Importantly, SPCA2-mediated Ca2＋ signaling is uncoupled from its conventional role of Ca2＋-ATPase and independent of store-operated Ca2＋ signaling pathway. SPCA2-induced store-independent Ca2＋ entry （SICE） plays essential roles in many important physiological processes, while unbalanced SICE leads to enhanced cell proliferation and tumorigenesis. Finally, we have summarized the clinical implication of SICE in oral cancer prognosis and treatment. Inhibition of SICE may be a new target for the development of cancer therapeutics.
基金supported by grants from the National Natural Science Foundation of China(No.30871122,No.81072684)
文摘Store-operated Ca2＋ channels （SOCs） are plasma membrane Ca2＋ permeable channels activated by depletion of intracellular Ca2＋ store. Ca2＋ entry through SOCs is known as store-operated Ca2＋ entry （SOCE）, which plays an important role in the functional regulation of airway smooth muscle cells （ASMCs）. Protein kinase C （PKC） has been shown to have an activating or inhibiting effect on SOCE, depending on cell types and PKC isoforms that are involved. In ASMCs, the effect of PKC on SOCE has not been elucidated so far. In this study, the role of PKC in the activation of SOCE in rat ASMCs was examined by using Ca2＋ fluorescence imaging technique. The results showed that acute application of PKC activators PMA and PDBu did not affect SOCE induced by the sarcoplasmic reticulum Ca2＋-ATPase （SERCA） inhibitor thapsigargin. The non-selective PKC inhibitor chelerythrine significantly inhibited thapsigargin- and bradykinin-induced SOCE. RT-PCR assay identified PKCα, δ and ε isoforms in rat ASMCs. PKCα-selective inhibitor G6976 and PKCε-inhibiting peptide Epsilon-V1-2 had no effect on SOCE; by contrast, PKCδ-selective inhibitor rottlerin attenuated SOCE dramatically, suggesting that PKCδ was the major PKC isoform involved in the activation of SOCE in ASMCs. Moreover, PKC down-regulation by extended exposure to high doses of PMA or PDBu also reduced SOCE, confirming the essential role of PKC in the activation of SOCE in ASMCs. In addition, PKC down-regulation did not influence the expression of stromal interaction molecule 1 （STIM1） and Orai1, two elementary molecules in the regulation and activation of SOCs. These results identified PKCδ as an essential PKC isoform involved in the activation of SOCE, and confirmed that PKC regulates the function of ASMCs in a SOCE-dependent manner.
基金supported by NIH R01-CA185055(to Zui Pan)Chaochu Cui received postgraduate student training of internationalization level promotion program from Sun Yat-sen University(02300-52114000)
文摘The intracellular calcium ions(Ca^(2+)) act as second messenger to regulate gene transcription,cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca^(2+)homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis,progression and metastasis. Targeting derailed Ca^(2+)signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca^(2+)channels, transporters and Ca^(2+)-ATPases,which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca^(2+)channels/transporters or Ca^(2+)-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for researchinto the understanding of cellular mechanisms underlying the regulation of Ca^(2+)signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca^(2+)channels or transporters.
