Introduction

Calcium plays vital function as a cellular molecules controlling several biological function such as transcription, signal transduction, cell proliferation and survival (Prakriya, 2020). The disruption in calcium homeostasis could contribute to oncogenesis (Gross et al., 2020). Store-operated calcium entry (SOCE) play pivotal roles in carcinogenesis in which the main regulator of this event is the Stromal interaction molecule 1 (STIM1) gene. Dysregulation of STIM1 was observed in multiple cancer which includes multiple myeloma (MM), colorectal cancer (CRC), and oral cancer, dysregulation led to the enhancement in cell survival via affecting regulation oncogenes for example Akt (Singh et al., 2020; J. Wang et al., 2015). Thus, STIM1 and SOCE is crucial in proper cellular function in which abrogation would contribute to cancer progression.

Furthermore, the role of STIM1 via SOCE induces ERK and Akt signaling pathways to induce melanoma and hepatocarcinoma (liver cancer) survivability and proliferation (Feldman et al., 2010; Umemura et al., 2014; Zhao et al., 2020). In addition, calcium/ROS interplay in carcinogenesis was also observed in other malignancies, in which calcium and ROS-dependent proliferative and survival signaling pathways were inducued (RAS/ERK,PI3K/Akt) (Feno et al., 2019; Perillo et al., 2020; Takahashi et al., 2018). Utilizing chemical inhibitors of SOCE such as the SKF96365, 2-APB, and RP4010, led to the suppression of cancer proliferative potential, clonal  expansion  and cell migration via the inhibition of Akt/mTOR, ERK1/2, and NFAT signaling (H. Cheng et al., 2016; Y. Cheng et al., 2018; Cui et al., 2017; Singh et al., 2020). Thus STIM1 serve as a lucrative target in alleviating oncogenic properties which could sanction further studies. 

STIM-1 Lanscape and the Store Operated Calcium Entry (SOCE)

Calcium (Ca2+) signals various cellular functions including transcription, cell division, motility, growth, and apoptosis. Calcium pumps and channels such as voltage-gated channels (VGCC), ligand-gated channels (LGC), store-operated channels (SOC), transient receptor potential channels (TRP), and mechanically gated channels plays pivotal role in maintaining Ca2+ homeostasis. SOCE is considered one of the main route of calcium into cells and is induced when depletion Ca2+ occurs within the endoplasmic reticulum (ER). SOCE has two counterparts: the ER part in which ER membrane contains the Ca2+ sensing STIM proteins, and the plasma membrane part containing the Orai subunits.

The STIM proteins, have a structure with an N-terminal luminal domain and a C-terminal cytoplasmic domain. The luminal part of STIM1 consists of a canonical and non-canonical EF-hand region connected to a sterile-a motif (SAM). The canonical EF-hand, which is negatively charged binds Ca2+, acting as a sensor for the Ca2+ concentration within the ER. The trans-membrane (TM) domain (protein domains that penetrates cell membrane) of STIM1 connects the luminal region (inner endoplasmic reticulum) of STIM1 to the cytoplasmic domain offering flexibility for facilitation of  conformational changes of STIM1 upon activation (Lunz et al., 2019; Rosado et al., 2016; Muik et al., 2012). STIM1 form the major channel for calcium uptake into the ER.

On the other hand, the cytoplasmic domain consists of three coiled-coil CC domains (CC1, CC2, and CC3), a CRAC modulatory domain (CMD), and a serine/proline- and a lysine-rich region. STIM1 fragments that activates Orai are the the CRAC activation domain (CAD), the STIM Orai-activating region (SOAR), the Orai activating small fragment (OASF), and the coiled-coil domain-containing region b9 (Ccb9) containing the CC2 and CC3 domains. CC1 function mainly in keeping STIM1 in a tight confromation rendering it inactive when ER-Ca2+ stores are at maximum capacity, whereas CC2 and CC3 domains are responsible for Orai1 channel activation upon STIM1 activation (Lunz et al., 2019; Rosado et al., 2016; Muik et al., 2012). The influence of calcium over STIM1 activity relies heavily on the levels of Ca2+ ions in which this would trigger conformational changes on the protein enabling calcium balancing.

The Orai family of proteins consist of Orai1, Orai2, and Orai3. The Orai channel which is in a hexameric complex includes four transmembrane helices (TM1-TM4). The pore at the center of the Orai channel is formed rings of TM1 helices this is followed by rings of TM2 and TM3 and subsequently the third ring, formed by TM4. The Extended Transmembrane Orai1 N-terminal region (ETON) is the cytosolic TM1 proximal which represents the N-terminal (terminal protein structure containing the amine group) part of Orai, which extend the TM1 into the cytosol. TM2 and TM3 also expands into the cytosol, but to a lesser extent. The TM4 entending into the cytosol represents the C-termini (terminal protein structure containing the carboxyl group) having a highly conserved region (Lunz et al., 2019; Muik et al., 2012; Rosado et al., 2015). Orai1 works in synergy with STIM1 in controlling calcium uptake of cells which contributes to calcium homeostasis.

The intricate relationship between STIM1 and Orai1 is therefore cucial in maintaining calcium homeastasis. Since both are calcium channels and are located at different parts of the cells their structures play pivotal roles in maintaining the balance of calcium levels. Thus a disruption in either of these channels would definitely impair SOCE and calcium balancing which could trigger destabilization of crucial calcium dependent signalling events.

STIM-1 and ROS Interplay

Calcium signaling stimulates cellular ROS production and oxidants through the STIM1/ROS interplay in which this controls calcium-related protein and channels which is the IP3R, and the TRP channels (Dejos et al., 2020; Hempel & Trebak, 2017). In addition, the extent of calcium on mitochondrial ROS (mtROS) depends on the metabolic state of the mitochondria, Ca2+ overload in the mitochondira leads to the production of mtROS which is independent from its metabolic state (Görlach et al., 2015; Li et al., 2013). Moreover, ROS produced through the NADPH oxidases was also affected by Ca2+ ions, this could occur directly through calcium-binding domains of the oxidases which include NOX5, DUOX1, and DUOX2 or indirectly via activators within the cytoplasm such as the PKCß1 and S100A8/A9 proteins, as observed in NOX1 and NOX2 (Görlach et al., 2015, Bréchard et al., 2013). This further support the crucial interplay between STIM1 and ROS as Ca2+ ions are regulated by STIM1.

Relatively, in normal circumstances, oxidative stress induced Ca2+ overload within the cytoplasm and mitochondira through various mechanisms, such as the activation of IP3R in order to enhance Ca2+ release from ER where the ions will be shuttled to the mitochondria, oxidative stress stimulate Ca2+ influx via  redox-sensitive STIM1 cysteines residues (C49, C56), stimulating the TRP channels inducing Ca2+ influx and suppressed extrusion of Ca2+ within the cytoplasm through plasma membrane Ca2+ ATPase. These ROS-induced events lead to Ca2+ ions overload which could triggering anti-survival response leading to cell death. However, cancer could adapt to oxidative stress which leads to the maintenance of sub-lethal levels of ROS. Furthermore, this type of cellular adaptation of cancer cells was reported to be linked to ROS/Ca2+ interaction (Hempel & Trebak, 2017). Thus this further support the role of ROS in contributing to STIM1 function which indicates interplay between SOCE and ROS levels.

Adaptation to oxidative stress is often triggered by calcium overload as it was reported that calcium dependent anti-apoptotic signalling events trailed calcium accumulation (Dejos et al., 2020). Thus ROS and calcium synergy is crucial in the maintenance of cancer as an increase in the levels of ROS would trigger calcium accumulation leading to anti oncogenic effect.

STIM-1 in cancer networks

The role of STIM1 and Orai1 in SOCE regulation has been studied in several cancers in which this could contrbute to the proliferative potential (cellular doubling potential) and survivability (Ge et al., 2019; Jardin & Rosado, 2016; Liu et al., 2020). Evidence on the role played by SOCE proteins was observed in breast cancer in which STIM1 and Orai1 induces migration and metastasis (cancer cells ability to invade foreign bodyparts) (Yang et al., 2009). Moreover in glioblastoma a reduction in proliferation was observed upon knockdown of of STIM1 and Orai1 (G. Li et al., 2013; Vashisht et al., 2015) where this was also observed in renal cell carcinoma (Kim et al., 2014). Interestingly, knockdown of STIM1 could also induce cisplatin mediated apoptosis in non-small lung cell cancer (NSLC) a type of lung cancer where malignancy occurs on the bigger cells within the lungs which includes adernocarcinoma (cells that forms lining of the lungs, squamous cell carcinoma (cells from the surface of bronchi) and large cell carcinoma (all over the lungs) (Herbst et al., 2018).  Thus a strong influence of STIM1 over several suggests a pivotal role of STIM1 over cancer regulation

Moreover, in support of the pivotal nature of STIM1, knockdown (suppression of gene) of this gene could depreciate STIM1 influence over SOCE  (Ge et al., 2019; W. Li et al., 2013). Additionally, STIM1 role in pancreatic adenocarcinoma cell lines could play anti-apoptotic (anti-programmed cell death) role, the suppression of STIM1 sensitized cells towards 5-fluorouracil (5-FU) (chemotherapy drug) or gemcitabine (chemotherapy drug)  in which this leads to apoptosis (Kondratska et al., 2014). Moreover, it was observed that Akt mediated STIM1 influence on hepatocarcinoma proliferative potential and survivability also occurs, in which AKT induce STIM1 and SOCE activity towards these phenotypes (biological characteristic) (Zhao et al., 2020). Furthermore, STIM1 suppression in melanoma cells led to the inactivation of Akt, which made the cells more susceptible towards apoptosis (Feldman et al., 2010). Additionaly, it was also reported that STIM1 and SOCE promotes cellullar proliferation in human melanoma by activating CaMKII/Raf-1/ERK signaling (Umemura et al., 2014). Thus, aside fron STIM1 direct effects towards cancer phenotypes, the gene could also interacts with other gene in promoting cancer phenotype.

The intricate relation between STIM1 and oncogenic properties is pivotal in maintaining oncogenic phenotypes. STIM1 interplay with various crucial signalling pathways in cancer further support the notion that STIM1 influence over SOCE and calcium levels are crucial in the pathogenesis of various cancers.

STIM-1 in Hematologic Malignancies

Studies on STIM1 and SOCE in hematological malignancies are still elementary. Elevated STIM1 and Orai1 expression was observed in Multiple Myeloma cell lines, in which the inhibition of STIM1 and Orai1 suppressed cell growth and leads to cell cycle arrest (W. Wang et al., 2018). Additionally, deleting STIM1 and STIM2 in T cell acute lymphoblastic leukemia (T-ALL) which is a type of hematologic malignancy usually resulting from the aggresive growth of malignant neoplasm of the bone marrow, and subsequent transplant of the STIM1 and STIM2 deleted T-ALL in mice prolonged survivability, reducing the necroinflammatory (inflamation caused by necrotic cell death) response in organs infiltrated with leukemic cells, down-regulation in pro-inflammatory pathways in leukemic T lymphoblasts was also observed (Saint Fleur-Lominy et al., 2018). This suggest that STIM1 could contribute to the aggressiveness of hematologic malignancies.

Morever, in myeloid leukemia (HL-60), Orai1 and Orai2 were found to affect cell proliferation and cell migration (Diez-Bello et al., 2017). Involvement of STIM and Orai was observed to substantially affect hematological malignancies as crucial cellular phenotype responded to changes in STIM1 and Orai levels. In another study, it was reported that Orai 3 could contribute to Tipifarnib (chemotherapy drug) mediated cell death in myeloid leukemia cells in which Orai3 expression were elevated in Tipifarnib-sensitive compared to Tipifarnib-insensitive leukemic cells (Vashisht et al., 2015).  Thus, STIM1 and its associate protein plays pivotal role in hematologic malignancies

Adding to this notion, a study performed on Non-Hodgkin B lymphoma cells showed that STIM1 and Orai1 could significantly influence the invasion and migration of diffuse large B cell lymphoma (DLBCL) which is a type of hematologic malignancy that affect the B lymphocyte resulting in enlarged lymphnodes (Latour et al., 2017; Tilly et al., 2015). Orai1 expression was found to be higher than STIM1 chronic myeloid leukemia with Bcr-Abl, which could explain the reduction in SOCE by lowering STIM1/Orai1 binding (Cabanas et al., 2018). The intricate correlation of STIM-1 and its cofactors in hematologic malignancies could still be explored to further understand the mechanism of STIM1 on SOCE activity of this type of cancer.

Although STIM1/Orai levels in various hematologic malignancies were measured, a definite correlation is yet to be drawn or studied. Therefore, a more in-depth study on the mechanism of STIM1 elevation could help in further elucidating the function of STIM1/Orai in hematologic malignancies. Thus, mechanism behind  the elevation of these proteins in hematologic could serve as a therapeutic avenue for targeting.

Conclusion

In conclusion, elucidation of  STIM-1 could act as a lucrative target in studying the effects of SOCE and ROS homeostasis which could enable cancer alleviation. Understanding the interplay between STIM1, SOCE and ROS could also be of interest as these could signal crucial event within the cancer environment which could lead to cancer progression. Furthermore, the effects of STIM1 in hematologic malignancies could be further studied to elucidate on the contribution of this genes towards the pathogenesis (disease development) of hematologic malignancies.

Author Contributions

R.B.S.M.N. M. conceptualized and designed the study. A.A., E.S.S.A., N.A.A.R., E.J.M., N.M.Y. collected and analyzed the data. drafted the manuscript. All authors critically reviewed and approved the final version.

Acknowledgment

The authors acknowledged the Ministry of Higher Education, Malaysia for supporting this work via awarding the Fundamental Research Grant Scheme (Project Code: FRGS/1/2021/SKK03/USM/02/3) and for the support provided by Universiti Sains Malaysia

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