Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Hu, Guolin; Zhang, Jialü; Xu, Feifei; Deng, Huan; Zhang, Weiwei; Kang, Shijun; Liang, Wenjie

doi:10.1111/cas.13563

Cited by 33 publications

(23 citation statements)

References 30 publications

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“…It has been reported that MEK/ERK signaling pathway plays an important role in controlling cell proliferation, differentiation, and apoptosis. Previous experiments have demonstrated that the expression of MEK/ERK could protect cells, promote proliferation, and prevent cell apoptosis [ 7 , 8 ]. Reduction of the ERK pathway in islet and MIN6 cells was associated with apoptosis [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Wushenziye Formula Inhibits Pancreatic β Cell Apoptosis in Type 2 Diabetes Mellitus via MEK-ERK-Caspase-3 Signaling Pathway

Tian

Chang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Background Wushenziye formula (WSZYF), composed of Radix Polygoni Multiflori Preparata, Mori fructus, Mori folium, and Cassiae semen, is effective in the treatment of type 2 diabetes mellitus (T2DM). Aim In this study, we aimed to explore the effects and the underlying mechanisms of WSZYF on inhibiting pancreatic β cell apoptosis and improving insulin resistance (IR) in T2DM. Methods A T2DM model was induced by Goto-Kakizaki diabetes prone rats. Cell apoptosis model was induced in MIN6 cells. Results In vivo, WSZYF decreased fasting blood glucose (FBG), insulin concentration, insulin resistance index, triglyceride (TG), total cholesterol (TC), and free fatty acids (FFA) in T2DM rats. Meanwhile, WSZYF ameliorated impairments in the morphology and structure of pancreatic tissues. In vitro, WSZYF enhanced cell viability and promoted insulin secretion in the apoptosis model of MIN6 cells. Furthermore, WSZYF modulated the expressions of apoptosis-related molecules by increasing the expressions of MEK1/2, p-MEK1/2, ERK1/2, and p-ERK1/2 and decreasing the cleaved-caspase-3 expression. Conclusion These findings indicate that WSZYF may become a new drug candidate in the treatment of T2DM and its antidiabetic mechanism is probably inhibiting pancreatic β cell apoptosis by modulating the MEK-ERK-Caspase-3 signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Wushenziye Formula Inhibits Pancreatic β Cell Apoptosis in Type 2 Diabetes Mellitus via MEK-ERK-Caspase-3 Signaling Pathway

Tian

Chang

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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“…Our results showed that HO-1 enhanced autocrine action of Gas6 in MM cell lines and CD138 + myeloma cells, but the function of HO-1 in Gas6 secretion by bone marrow stroma cells is unclear. Further studies need to explore whether HO-1 regulate bone marrow stroma cells to produce Gas6 and unravel the functions of AGING ERK1/2 signaling is involved in regulating a variety of cancer cells functions, such as cell proliferation, migration, differentiation and apoptosis [37][38][39][40]. Mandal R et al illustrated that ERK1/2 signaling was activated in about half of MM patients and was considered to be a potential target in MM [41].…”

Section: Discussionmentioning

confidence: 99%

Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis

Zhang

Wang

et al. 2020

Aging

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Chemoresistance is still a critical challenge for efficient treatment of multiple myeloma (MM) during the bortezomib-based chemotherapy. Recent studies have suggested that heme oxygenase-1 (HO-1) is involved in apoptosis, proliferation and chemoresistance in cancer cells. Here we aim to investigate the role and mechanism of HO-1 in bortezomib-sensitivity to myeloma cells. In the study population, we found that HO-1 was highly expressed in CD138 + primary myeloma cells, which was positively associated with Gas6 expression and Gas6 plasma levels in MM patients. Downregulation of HO-1 using pharmacological inhibitor ZnPPIX or siRNA knockdown significantly enhanced myeloma cell sensitivity to bortezomib in human primary CD138 + cells, U266 and RPMI8226 cell lines. Mechanistically, HO-1 regulated Gas6 production via ERK/STAT3 axis. Combination with HO-1 inhibition increased bortezomib-induced apoptosis and antiproliferative effects via suppressing Gas6 production. These findings suggest that combination of bortezomib and HO-1 inhibitor may serve as a promising therapeutic target against bortezomib-resistant MM. www.aging-us.com 6612 AGING with chemoresistance [13]. However, the underlying mechanisms between HO-1 and chemoresistance remain unclear. Growth arrest-specific gene 6 (Gas6) is a 75 kDa secreted protein containing an N-terminal gamma-carboxyglutamic acid domain [14]. Gas6 has been implicated in promoting proliferation, migration and survival of multiple types of cancer cells, including breast, melanoma, ovarian, renal and prostate cancers [15-19]. Besides, emerging evidence indicate that high expression of Gas6 is associated with a poor prognosis in hematologic malignancies. Patients with acute myeloid leukemia expressing Gas6, especially those aged ≥60 years, more often fail to achieve a complete remission and have shorter disease-free and overall survive than those without Gas6 expression [20]. In addition, aberrant Gas6 secretion promotes acute myeloid leukemia cells growth and chemoresistance [21]. It suggests that Gas6 represents a critical factor for chemoresistance. However, whether HO-1 mediates the sensitivity of MM to bortezomib via Gas6 is still unknown and remains to be investigated. We hypothesized that HO-1 inhibition downregulates Gas6 to overcome adaptive bortezomib resistance in MM, providing a potential target against drug resistance in the treatment of MM. Additionally, we aimed at investigating the molecular mechanism how HO-1 regulates Gas6 in bortezomib-resistant myeloma cells. RESULTS High HO-1 expression is associated with increased Gas6 expression in patients with MM

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“…The biological role of STOML2 is to regulate mitochondrial membrane stability and function; under mitochondrial stress, it interacts with prohibitins, molecular chaperones in respiratory chain complexes [7]. Hu et al reported that STOML2 activated MEK/ERK signaling and suppressed mitochondrial apoptosis pathway in HeLa cervical cancer cells, through altering the ability of mitochondria to buffer Ca 2+ and shape cytosolic Ca 2+ signal [41]. Recent related studies also implied that, STOML2 modulated tumor malignancy via IL6-Stat3 pathway in head and neck squamous cell carcinoma [19].…”

Section: Discussionmentioning

confidence: 99%

STOML2 Interacts with PHB through Activating MAPK Signaling Pathway to Promote Colorectal Cancer Proliferation.

Chen

et al. 2020

Preprint

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BackgroundOverexpression of STOML2 has been widely reported in a variety of cancer, yet few has detailed its function and regulatory mechanism. This study aims to reveal the clinicopathologic significance and oncologic function of STOML2 in colorectal cancer, explore its specific mechanism by means of yeast two-hybrid assay and bioinformatics.MethodsExpression level of STOML2 in normal colon and CRC tissue from biobank in Nanfang Hospital was detected by pathologic methods. The malignant proliferation of CRC induced by STOML2 was validated via gain-of-function and loss-of-function experiments, with novel techniques applied, such as organoid culture, orthotopic model and endoscopy monitoring. Yeast two-hybrid assay was conducted to screen interacting proteins of STOML2, followed by bioinformatics to predict biological process and signaling pathway of candidate proteins. Target protein with most functional similarity to STOML2 was validated with co-immunoprecipitation, and immunofluorescence were conducted to co-localize STOML2 and PHB. Pathway regulated by STOML2 was detected with immunoblotting, and subsequent experimental therapy was conducted with RAF inhibitor Sorafenib.ResultsSTOML2 was significantly overexpressed in colorectal cancer and its elevation was associated with unfavorable prognosis. Knockdown of STOML2 suppressed proliferation of colorectal cancer, thus attenuated subcutaneous and orthotopic tumor growth, while overexpressed STOML2 promoted proliferation in cell lines and organoids. A list of 13 interacting proteins was screened out by yeast two-hybrid assay. DTYMK and PHB were identified to be most similar to STOML2 according to bioinformatics in terms of biological process and signaling pathways; however, co-immunoprecipitation confirmed interaction between STOML2 and PHB, rather than DTYMK, despite its highest rank in previous analysis. Co-localization between STOML2 and PHB was confirmed in cell lines and tissue level. Furthermore, knockdown of STOML2 downregulated phosphorylation of RAF1, MEK1/2, ERK1/2 and ELK1 on the MAPK signaling pathway, indicating common pathway activated by STOML2 and PHB in colorectal cancer proliferation.ConclusionsThis study demonstrated that in colorectal cancer, STOML2 expression is elevated and interacts with PHB through activating MAPK signaling pathway, to promote proliferation both in vitro and in vivo. In addition, combination of screening assay and bioinformatics marks great significance in methodology to explore regulatory mechanism of protein of interest.

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Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells

Cited by 33 publications

References 30 publications

Wushenziye Formula Inhibits Pancreatic β Cell Apoptosis in Type 2 Diabetes Mellitus via MEK-ERK-Caspase-3 Signaling Pathway

Wushenziye Formula Inhibits Pancreatic β Cell Apoptosis in Type 2 Diabetes Mellitus via MEK-ERK-Caspase-3 Signaling Pathway

Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis

STOML2 Interacts with PHB through Activating MAPK Signaling Pathway to Promote Colorectal Cancer Proliferation.

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