The distinct role of STIM1 and STIM2 in the regulation of store‐operated Ca²⁺ entry and cellular function

Abstract

Stromal interaction molecules STIM1 and STIM2 are endoplasmic reticulum (ER) Ca2+ sensors that initiate store‐operated Ca 2+ entry (SOCE). The roles of STIM1‐mediated SOCE in cancer biology have been highlighted in different types of cancer, but that of STIM2 is unknown. By the model of cervical cancer, here we focus on the cooperative regulation of SOCE by STIM proteins and their distinct roles in cellular function. Immunofluorescent stainings of surgical specimens of cervical cancer show that STIM1 and STIM2 are abundant in tumor tissues, but STIM1 is the major ER Ca 2+ sensor identified in the invasive front of cancer tissues. STIM1 or STIM2 overexpression in cervical cancer SiHa cells induces an upregulated SOCE. Regarding cellular function, STIM1 and STIM2 are necessary for cell proliferation, whereas STIM1 is the dominant ER Ca 2+ sensor involved in cell migration. During SOCE, STIM1 is aggregated and translocated towards the Orai1‐containing plasma membrane in association with the microtubule plus‐end binding protein EB1. In contrast, STIM2 is constitutively aggregated without significant trafficking or association with microtubules. These results show the distinct role of STIM1 and STIM2 in SOCE and cellular function of cervical cancer cells.

Store-Operated Ca2+ Entry in Tumor Progression: From Molecular Mechanisms to Clinical Implications

“…This mechanism was challenged by a recent study on HeLa cells showing that EB1 binding may delay STIM1 translocation during ER Ca 2+ loss, prevent overloading of ER Ca 2+ , and avoid excessive activation of SOCE [26]. However, a very recent study on cervical cancer SiHa cells showed that STIM1 and STIM2 displayed different kinetic characteristics during SOCE activation [27]. Results from high-resolution imaging and total internal reflection fluorescence microscopy of living cells demonstrated that a decrease in ER Ca 2+ levels promoted the oligomerization, EB1 association and membrane translocation of STIM1.…”

“…Aberrant overexpression of STIM1 or Orai1 and thus upregulated SOCE activity have been observed in several types of human cancers. For instance, STIM1 or Orai1 is overexpressed in tumor tissues when compared with noncancerous or precancerous tissues in patients with breast [29], cervical [24,27,30,31], colorectal [32,33], liver [34], lung [35], clear cell renal cancers [36], or multiple myeloma [37]. Furthermore, the expression of Orai1/STIM1, as well as SOCE activity, is enhanced in cisplatin-resistant ovarian carcinoma cells when compared with the therapy-sensitive parental cells [38].…”

“…Interestingly, the specific distribution of overexpressed STIM1 in the invasive tumor front was identified in a recent study on human cervical cancer [41]. Results from the simultaneous immunostaining of STIM1 and STIM2 showed that, despite the overexpression of both isoforms in tumor tissues, STIM1 is the principle ER Ca 2+ -sensing molecule detected in the invasive tumor front [27]. These imply that STIM1 is associated with both tumor growth and invasion, whereas STIM2 is mainly correlated with tumor growth.…”

Microtubules Stabilization by Mutant Spastin Affects ER Morphology and Ca2+ Handling

“…It has been demonstrated that after Ca 2+ store depletion, STIM oligomerizes and redistributes to predetermined foci in the peripheral ER (Luik et al, 2008). STIM binds the MT plus-end binding protein EB1, which facilitates TAC-dependent STIM translocation toward the PM (Liou et al, 2007;Honnappa et al, 2009;Chen et al, 2013Chen et al, , 2019Tsai et al, 2014). At the ER-PM junctions, STIM interacts with Orai channels to promote influx of extracellular Ca 2+ into the ER (Liou et al, 2007;Grigoriev et al, 2008;Galán et al, 2011).…”

Met Mutation is a Potential Therapeutic Target for Advanced Endometrial Cancer 

“…In April 2017, authenticated endometrial cancer cell lines, RL95-2 and KLE, were purchased from the American Type Culture Collection. Cell functions on proliferation, migration, and invasion were performed as previously described 14 . Brie y, the RL95-2 and KLE cell lines transfected with wild-type and mutant c-MET were seeded into 96-well plates (5 × 10 3 / well) with 100 µl of culture medium and incubated at 37ºC with 5% CO 2 .…”