Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression

Bharadwaj, Uddalak; Marin-Muller, Christian; Li, Min; Chen, Changyi; Yao, Qizhi

doi:10.1186/1476-4598-10-106

Cited by 151Pancreatic and Hepatic Oncology ResearchCell death mechanisms and regulationSignaling Pathways in Disease

Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression

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Bharadwaj, Uddalak, Marin-Muller, Christian, Li, Min, Chen, Changyi, Yao, Qizhi·2011·Molecular Cancer

DOI 10.1186/1476-4598-10-106PMC PMC3175472

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Abstract

Background: Previous studies showed that mesothelin (MSLN) plays important roles in survival of pancreatic cancer (PC) cells under anchorage dependent/independent conditions as well as resistance to chemotherapy. The recent success of intratumorally-injected adeno-encoded, chemo/radiation-inducible-promoter driven hTNF-α, (TNFerade) + gemcitabine in pre-clinical models of PC have renewed interest in use of TNF-α as a therapeutic component. To help find additional factors which might affect the therapy, we examined the resistance of MSLN-overexpressing pancreatic cancer cell lines to TNF-α-induced growth inhibition/apoptosis. Methods: Stable MSLN overexpressing MIA PaCa-2 cells (MIA-MSLN), stable MSLN-silenced AsPC-1 cells (AsPC-shMSLN) and other pancreatic cells (MIA-PaCa2, Panc 28, Capan-1, BxPC3, PL 45, Hs 766T, AsPC-1, Capan-2, Panc 48) were used. NF-κB activation was examined by western blots and luciferase reporter assay. TNF-α induced growth inhibition/apoptosis was measured by MTT, TUNEL assay and caspase activation. IL-6 was measured using luminex based assay. Results: Compared to low endogenous MSLN-expressing MIA PaCa-2 and Panc 28 cells, high endogenous MSLN-expressing Capan-1, BxPC3, PL 45, Hs 766T, AsPC-1, Capan-2, Panc 48 cells were resistant to TNF-α induced growth inhibition. Stable MSLN overexpressing MIA-PaCa2 cells (MIA-MSLN) were resistant to TNF-α-induced apoptosis while stable MSLN-silenced AsPC1 cells (AsPC-shMSLN) were sensitive. Interestingly, TNF-α-treated MIA-MSLN cells showed increased cell cycle progression and cyclin A induction, both of which were reversed by caspase inhibition. We further found that MIA-MSLN cells showed increased expression of anti-apoptotic Bcl-XL and Mcl-1; deactivated (p-Ser 75 ) BAD, and activated (p-Ser 70 ) Bcl-2. Constitutively activated NF-κB and Akt were evident in MIA-MSLN cells that could be suppressed by MSLN siRNA with a resultant increase in sensitivity of TNF-α induced apoptosis. Blocking NF-κB using IKK inhibitor wedelolactone also increased sensitivity to TNF-α-mediated cytotoxicity with concomitant decrease in Mcl-1. Blocking Akt using PI3K inhibitor also had a likewise effect presumably affecting cell cycle. MIA-MSLN cells produced increased IL-6 and were increased furthermore by TNF-α treatment. SiRNA-silencing of IL-6 increased TNF-α sensitivity of MIA-MSLN cells. Conclusions: Our study delineates a MSLN-Akt-NF-κB-IL-6-Mcl-1 survival axis that may be operative in PC cells, and might help cancer cells' survival in the highly inflammatory milieu evident in PC. Further, for the success of TNFerade + gemcitabine to be successful, we feel the simultaneous inhibition of components of this axis is also essential.

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MSLN confers pancreatic cancer cell resistance to TNFα-induced apoptosis through NF-κB activation and the enhanced expression of IL-6.
“It confers pancreatic cancer cell resistance to TNFα-induced apoptosis through NF-κB activation and the enhanced expression of IL-6 (319).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [319]

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Mesothelin-targeted CAR-T cell therapy for solid tumors
Klampatsa, A., Dimou, V., & Albelda, S. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2021.1843628 · Cited by 130 · see citing works
“overexpression in pancreatic cancer cell lines has been associated with resistance to tumor necrosis factor-alpha (TNF-α)mediated apoptosis [48], anoikis-induced apoptosis [49] and resistance to paclitaxel treatment [50].”
Background
Mesothelin as a biomarker for targeted therapy
Lv, J., & Li, P. (2019) · Biomarker Research · doi:10.1186/s40364-019-0169-8 · Cited by 126 · see citing works
“The overexpression of MSLN could activate the NFκB, MAPK, and PI3K pathways and subsequently induce resistance to apoptosis [10] or promote cell proliferation, migration, and metastasis by inducing the activation and expression of MMP7 [9] and MMP9 [5].”
Background
Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy
Mercogliano, M. F., Bruni, S., Mauro, F. L., Elizalde, P. V., & Schillaci, R. (2021) · Cancers · doi:10.3390/cancers13030564 · Cited by 134 · see citing works
CAR-T Cell Therapy for Breast Cancer: From Basic Research to Clinical Application
Yang, Y.-H., Liu, J.-W., Lu, C., & Wei, J.-F. (2022) · International Journal on Biological Sciences · doi:10.7150/ijbs.70120 · Cited by 112 · see citing works
“Overexpression of MSLN constitutively activates the intracellular signaling pathways (such as MAPK, PI3K, and NF-kB) to promote tumor development and progression[99, 101].”
Background
Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells
He, X., Wang, L., Riedel, H., Wang, K., Yang, Y. S., Dinu, C. Z., & Rojanasakul, Y. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0633-8 · Cited by 132 · see citing works
“Preclinical studies showed that MSLN is involved in cell proliferation, anoikis resistant and survival [10–12], and its downregulation promotes drug-induced apoptosis and chemosensitivity [13, 14].”
Background
Regulatory mechanisms and clinical perspectives of miRNA in tumor radiosensitivity
Zhao, L., Bode, A. M., Cao, Y., & Dong, Z. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs235 · Cited by 114 · see citing works
Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis
Koyama, Y., Wang, P., Liang, S., Iwaisako, K., Liu, X., Xu, J., Zhang, M., Sun, M., Cong, M., Karin, D., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88845 · Cited by 111 · see citing works
Mesothelin Expression in Triple Negative Breast Carcinomas Correlates Significantly with Basal-Like Phenotype, Distant Metastases and Decreased Survival
Tozbikian, G., Brogi, E., Kadota, K., Catalano, J. P., Akram, M. M., Patil, S., Ho, A., Reis-Filho, J., Weigelt, B., Norton, L., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114900 · Cited by 97 · see citing works
“Mesothelin expression increases resistance to TNFa-induced apoptosis through Akt/PI3K/NF-kB activation and IL-6/Mcl-1 expression in pancreatic carcinoma cell lines [12].”
Background
Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors
Weidemann, S., Gagelmann, P., Gorbokon, N., Lennartz, M., Menz, A., Luebke, A., Kluth, M., Hube-Magg, C., Blessin, N., Fraune, C., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9040397 · Cited by 95
Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers
Hagemann, U. B., Ellingsen, C., Schuhmacher, J., Kristian, A., Mobergslien, A., Cruciani, V., Wickstroem, K., Schatz, C. A., Kneip, C., Golfier, S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3476 · Cited by 115 · see citing works
A Tumorigenic Factor Interactome Connected Through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer
Marin-Muller, C., Li, D., Bharadwaj, U., Li, M., Chen, C., Hodges, S., Fisher, W., Mo, Q., Hung, M., & Yao, Q. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3776 · Cited by 85
Self-citation
IL-6 roles - Molecular pathway and clinical implication in pancreatic cancer - A systemic review.
Pop, V., Seicean, A., Lupan, I., Samașca, G., & Burz, C. (2017) · Immunology Letters · doi:10.1016/j.imlet.2016.11.010 · Cited by 76 · see citing works
Luminal membrane expression of mesothelin is a prominent poor prognostic factor for gastric cancer
Einama, T., Homma, S., Kamachi, H., Kawamata, F., Takahashi, K., Takahashi, N., Taniguchi, M., Kamiyama, T., Furukawa, H., Matsuno, Y., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.235 · Cited by 74
“In addition, mesothelin-activated nuclear factor-kappaB (NF-kB) induces elevated interleukin (IL)-6 expression, which acts as a growth factor to support pancreatic cancer cell survival/proliferation through a novel auto/paracrine IL-6/soluble IL-6R trans-signalling (Bharadwaj et al, 2011a, b).”
Background
Clusterin confers resistance to TNF-alpha-induced apoptosis in breast cancer cells through NF-kappaB activation and Bcl-2 overexpression
Wang, Y., Wang, X.-G., Zhao, H., Liang, B., & Du, Q.-H. (2012) · Journal of chemotherapy · doi:10.1179/1973947812y.0000000049 · Cited by 72 · see citing works
The Impact of Mesothelin in the Ovarian Cancer Tumor Microenvironment
Hilliard, T. S. (2018) · Cancers · doi:10.3390/cancers10090277 · Cited by 71 · see citing works
Inflammatory cytokines regulate the expression of glycosyltransferases involved in the biosynthesis of tumor-associated sialylated glycans in pancreatic cancer cell lines.
Bassagañas, S., Allende, H., Cobler, L., Ortiz, M. R., Llop, E., de Bolós, C., & Peracaula, R. (2015) · Cytokine · doi:10.1016/j.cyto.2015.04.006 · Cited by 62
Effective response of doxorubicin-sensitive and -resistant breast cancer cells to combinational siRNA therapy
Aliabadi, H. M., Maranchuk, R. A., Kucharski, C., Mahdipoor, P., Hugh, J. C., & Uludağ, H. (2013) · Journal of Controlled Release · doi:10.1016/j.jconrel.2013.08.012 · Cited by 56 · see citing works
Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation
Coelho, R., Ricardo, S., Amaral, A. L., Huang, Y.-L., Nunes, M., Neves, J. P., Mendes, N., López, M. N., Bartosch, C., Ferreira, V., et al. (2020) · Oncogenesis · doi:10.1038/s41389-020-00246-2 · Cited by 55 · see citing works
Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma
Chen, H.-Y., Lin, L.-T., Wang, M.-L., Lee, S.-H., Tsai, M., Tsai, C., Liu, W.-H., Chen, T.-C., Yang, Y.-P., Lee, Y.-Y., et al. (2016) · OncoTarget · doi:10.18632/oncotarget.9890 · Cited by 55 · see citing works
“For instance, IL-6-induced PI3K/AKT activation was essential for anti-apoptotic signaling cascade, which has long be linked to therapeutic resistance [19].”
Background
Plant coumestans: recent advances and future perspectives in cancer therapy.
Nehybová, T., Šmarda, J., & Beneš, P. (2014) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520614666140713172949 · Cited by 54
“Wedelolactone senzitizes pancreatic cancer cells to proapoptotic effects of TNFα by inhibiting the NFκB activity and decreasing expression of Mcl-1, a member of the Bcl-2 protein family [134].”
Background
Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells
Wang, K., Bodempudi, V., Liu, Z., Borrego-Diaz, E., Yamoutpoor, F., Meyer, A. C., Woo, R. A., Pan, W., Dudek, A., Olyaee, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033214 · Cited by 53 · see citing works
Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53-dependent and -independent signal pathway
Zheng, C.-N., Jia, W., Tang, Y., Zhao, H., Jiang, Y., & Sun, S.-C. (2012) · Journal of experimental & clinical cancer research : CR · doi:10.1186/1756-9966-31-84 · Cited by 50 · see citing works
“Otherwise, knockdown of mesothelin sensitized pancreatic cancer cells to radiation and TNF-a-induced apoptosis [17,18].”
Background
Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis
Al‐Lamki, R. S., Lu, W., Manalo, P. B., Wang, J., Warren, A. Y., Tolkovsky, A. M., Pober, J. S., & Bradley, J. R. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.184 · Cited by 48 · see citing works
Intracellular localization of mesothelin predicts patient prognosis of extrahepatic bile duct cancer
Kawamata, F., Kamachi, H., Einama, T., Homma, S., Tahara, M., MIYAZAKI, M., Tanaka, S., Kamiyama, T., Nishihara, H., Taketomi, A., et al. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1662 · Cited by 61 · see citing works
Single-cell and spatial transcriptome profiling reveal CTHRC1+ fibroblasts promote EMT through WNT5A signaling in colorectal cancer
Lu, Y., Chen, Y., Wang, Z., Shen, H.-Y., Xu, L., Huang, C., Tong, Y., Shao, Y., Zhang, H.-Q., & Fu, Z. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06236-5 · Cited by 45 · see citing works
Proteasomal Degradation of Mcl-1 by Maritoclax Induces Apoptosis and Enhances the Efficacy of ABT-737 in Melanoma Cells
Pandey, M., Gowda, K., Doi, K., Sharma, A. K., Wang, H.-G., & Amin, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078570 · Cited by 43 · see citing works
Free CA125 promotes ovarian cancer cell migration and tumor metastasis by binding Mesothelin to reduce DKK1 expression and activate the SGK3/FOXO3 pathway
Huo, Q.-Y., Xu, C., Shao, Y., Yu, Q., Huang, L.-H., Liu, Y.-D., & Bao, H. (2021) · International Journal on Biological Sciences · doi:10.7150/ijbs.52097 · Cited by 42
“In addition, MSLN protects cells from drug-induced apoptosis and mediates drug resistance in cancer [58,59,60].”
Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy
Ouladan, S., & Orouji, E. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-24-02081 · Cited by 48 · see citing works
Mesothelin‑targeted second generation CAR‑T cells inhibit growth of mesothelin‑expressing tumors in�vivo
Ye, L., Lou, Y., Lu, L., & Fan, X. (2018) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2018.7015 · Cited by 41 · see citing works
“It can activate nuclear factor-κB, mitogen-activated protein kinase and PI3K intracellular pathways that contribute to cell proliferation and resistance to apoptosis (60-62).”
Background
CAR T-cells for colorectal cancer immunotherapy: Ready to go?
Ghazi, B., Ghanmi, A. E., Kandoussi, S., Ghouzlani, A., & Badou, A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.978195 · Cited by 46 · see citing works
PD-1 silencing improves anti-tumor activities of human mesothelin-targeted CAR T cells.
Liu, G.-D., Zhang, Q., Li, D., Zhang, L.-S., Gu, Z., Liu, J., Liu, G.-P., Yang, M., Gu, J., Cui, X., et al. (2020) · Human Immunology · doi:10.1016/j.humimm.2020.12.002 · Cited by 40 · see citing works
From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma
Montemagno, C., Cassim, S., Pouysségur, J., Broisat, A., & Pagès, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114067 · Cited by 39 · see citing works
“MSLN signaling is also involved in the resistance to TNF-α-induced apoptosis through the activation of the Akt/PI3K/NFκB axis in PDAC [48].”
Background
Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma
Pantazopoulos, I., Boura, P., Xanthos, T., & Syrigos, K. (2012) · European Respiratory Journal · doi:10.1183/09031936.00226111 · Cited by 38 · see citing works
Metformin Antagonizes Ovarian Cancer Cells Malignancy Through MSLN Mediated IL-6/STAT3 Signaling
Yang, X., Huang, M., Zhang, Q., Chen, J., Li, J., Han, Q., Zhang, L., Li, J.-Q., Liu, S., Ma, Y., et al. (2021) · Cell Transplantation · doi:10.1177/09636897211027819 · Cited by 37 · see citing works
Amatuximab and novel agents targeting mesothelin for solid tumors
Baldo, P., & Cecco, S. (2017) · OncoTargets and Therapy · doi:10.2147/ott.s145105 · Cited by 37 · see citing works
“14,15 Importantly, in recent years, the activation and stimulation of immune reactions using engineered T-cells with chimeric antigen receptors (CARs) allowed the characterization of antigens, including MSLN, overexpressed in solid tumors and in several B-cell malignancies, including acute…”
A Novel PET Imaging Using 64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells
Kobayashi, K., Sasaki, T., Takenaka, F., Yakushiji, H., Fujii, Y., Kishi, Y., Kita, S., Shen, L.-H., Kumon, H., & Matsuura, E. (2015) · Journal of Immunological Research · doi:10.1155/2015/268172 · Cited by 36
“against Mesothelin Commonly Expressed on Cancer Cells Kazuko Kobayashi,1,2 Takanori Sasaki,3 Fumiaki Takenaka,3 Hiromasa Yakushiji,1 Yoshihiro Fujii,4 Yoshiro Kishi,4 Shoichi Kita,4 Lianhua Shen,1,5 Hiromi Kumon,2 and Eiji Matsuura1,3 1Department of Cell Chemistry, Okayama University Graduate School of Medicine, Denti…”
Background
C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma
Kawamata, F., Homma, S., Kamachi, H., Einama, T., Kato, Y., Tsuda, M., Tanaka, S., Maeda, M., Kajino, K., Hino, O., et al. (2013) · Journal of gastroenterology · doi:10.1007/s00535-013-0773-6 · Cited by 35 · see citing works
“Many researchers have investigated the role of the mesothelin expression in tumor biology, and demonstrated the importance of mesothelin expression for tumor progression in vitro [17-20] and in vivo [20, 21], and we recently explored that the luminal membrane expression of mesothelin was related to an unfavorable pati…”
Background
Targeting solid tumor antigens with chimeric receptors: cancer biology meets synthetic immunology
Kembuan, G. J., Kim, J. Y., Maus, M. V., & Jan, M. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.01.003 · Cited by 37 · see citing works
Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity
Yang, Y., Vedvyas, Y., Alcaina, Y., Trumper, S. J., Babu, D. S., Min, I. M., Tremblay, J. M., Shoemaker, C. B., & Jin, M. M. (2024) · JCI Insight · doi:10.1172/jci.insight.186268 · Cited by 35 · see citing works
“Additionally, aberrant expression of MSLN has been associated with tumor aggressiveness, malignant transformation, increased invasion and metastasis, and resistance to apoptosis (3–6).”
The dark side of immunotherapy: pancreatic cancer
Mucciolo, G., Roux, C., Scagliotti, A., Brugiapaglia, S., Novelli, F., & Cappello, P. (2020) · Cancer Drug Resistance · doi:10.20517/cdr.2020.13 · Cited by 37 · see citing works
“MSLN contributes to cell proliferation and resistance to apoptosis([105]), and by activating matrix metalloproteases 9 (MMP-9)([104]) and MMP-7([106]), it can induce tumor cell migration and invasion.”
Background
MSLN Correlates With Immune Infiltration and Chemoresistance as a Prognostic Biomarker in Ovarian Cancer
Li, Y., Tian, W., Zhang, H., Zhang, Z., Zhao, Q., Chang, L., Lei, N., & Zhang, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.830570 · Cited by 31 · see citing works
“Studies have shown that overexpression of MSLN can activate the PI3K pathway and induce drug resistance in pancreatic cancer cells (19).”
Background
Nucleic acid combinations: A new frontier for cancer treatment
Remant Bahadur, K. C., Thapa, B., Valencia‐Serna, J., Aliabadi, H. M., & Uludağ, H. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.04.029 · Cited by 30 · see citing works
Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors.
Han, S., Latchoumanin, O., Wu, G., Zhou, G., Hebbard, L., George, J., & Qiao, L. (2017) · Cancer Letters · doi:10.1016/j.canlet.2016.12.037 · Cited by 31
“The natural function of mesothelin in normal tissues is unclear but recent studies hav e shown that over-expression of mesothelin on tumor tissues could facilitate cell proliferation, i vasion and metastasis, and confer tumor cells wit h resistance to apoptosis [51-54].”
Background
The Effect of Interleukin-6 (IL-6), Interleukin-11 (IL-11), Signal Transducer and Activator of Transcription 3 (STAT3), and AKT Signaling on Adipocyte Proliferation in a Rat Model of Polycystic Ovary Syndrome
Zhuang, Z., Pan, X., Zhao, K., Gao, W., Liu, J., Deng, T., & Qin, W. (2019) · Medical Science Monitor · doi:10.12659/msm.916385 · Cited by 30 · see citing works
“IL-6, regulated by AKT activity, has previously been shown to activate PI3K/AKT and the anti-apoptotic signaling cascade [21,22].”
Background
Antibody-drug conjugates in gynecologic malignancies.
Lee, E. K., & Liu, J. F. (2019) · Gynecologic Oncology · doi:10.1016/j.ygyno.2019.03.245 · Cited by 30
Biology of Mesothelin and Clinical Implications: A Review of Existing Literature
Hagerty, B. L., & Takabe, K. (2023) · World Journal of Oncology · doi:10.14740/wjon1655 · Cited by 25 · see citing works
“They went on to further establish an autocrine/paracrine mechanism of MSLN action whereby activation of nuclear factor kappa B (NF-κB) induced interleukin (IL)-6 release which then acts as a growth factor to support cell survival and proliferation [63, 64].”
Background
TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression.
Park, G.-B., & Kim, D. (2017) · Oncology Report · doi:10.3892/or.2017.5941 · Cited by 27 · see citing works
Immunotherapy-based targeting of MSLN + activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis
Nishio, T., Koyama, Y., Liu, X., Rosenthal, S. B., Yamamoto, G., Fuji, H., Baglieri, J., Li, N., Brenner, L. N., Iwaisako, K., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2101270118 · Cited by 29 · see citing works
“CA125 (mouse Muc16) is the only known ligand of MSLN and was reported to activate Src/Akt signaling in cancer cells (38, 39).”
Background
The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy
Liu, X., Deng, J., Zhang, R., Xing, J., Wu, Y., Chen, W., Liang, B., Xing, D., Xu, J., & Zhang, M. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1335252 · Cited by 28 · see citing works
Clinical impacts of mesothelin expression in gastrointestinal carcinomas.
Einama, T., Kawamata, F., Kamachi, H., Nishihara, H., Homma, S., Matsuzawa, F., Mizukami, T., Konishi, Y., Tahara, M., Kamiyama, T., et al. (2016) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v7.i2.218 · Cited by 25
Redox state alters anti‐cancer effects of wedelolactone
Beneš, P., Alexova, P., Knopfová, L., Španová, A., & Šmarda, J. (2012) · Environmental and Molecular Mutagenesis · doi:10.1002/em.21712 · Cited by 30 · see citing works
“Wedelolactone has been used as an inhibitor of the NFjB activity in numerous studies [Idris et al., 2009; Zheng et al., 2010; Bharadwaj et al., 2011].”
Method
The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review
Nichetti, F., Marra, A., Corti, F., Guidi, A., Raimondi, A., Prinzi, N., de Braud, F., & Pusceddu, S. (2018) · Targeted Oncology · doi:10.1007/s11523-018-0567-0 · Cited by 23 · see citing works
Mesothelin Expression in Gastric Adenocarcinoma and Its Relation to Clinical Outcomes
Han, S.-H., Joo, M., Kim, H.-S., & Chang, S. (2017) · Journal of Pathology and Translational Medicine · doi:10.4132/jptm.2016.11.18 · Cited by 23 · see citing works
“Bharadwaj et al.(23) reported that mesothelin expression increased resistance to tumor necrosis factor-α– induced apoptosis through Akt/phosphoinositide 3-kinase/nuclear factor κB activation.”
Background
Current status and innovative developments of CAR-T-cell therapy for the treatment of breast cancer
Marei, H. E. S., Bedair, K., Hasan, A., Al-Mansoori, L., Caratelli, S., Sconocchia, G., Gaiba, A., & Cenciarelli, C. (2025) · Cancer Cell International · doi:10.1186/s12935-024-03615-8 · Cited by 24 · see citing works
“The constitutive activation of intracellular signaling pathways (NF-kB, PI3K, and MAPK) by MSLN overexpression facilitates the formation and progression of tumors [72].”
Significance of mesothelin and CA125 expression in endometrial carcinoma: a retrospective analysis
Kakimoto, S., Miyamoto, M., Einama, T., Takihata, Y., Matsuura, H., Iwahashi, H., Ishibashi, H., Sakamoto, T., Hada, T., Suminokura, J., et al. (2021) · Diagnostic Pathology · doi:10.1186/s13000-021-01093-4 · Cited by 22
“Overexpression of mesothelin alone could constitutively activate the nuclear factorkappa B, mitogen-activated protein kinase, and phosphoinositide 3-kinase intracellular pathways, promoting cell proliferation and resistance to apoptosis [30].”
Background
GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets
Hussein, N. H., Amin, N. S., & Tayebi, H. E. E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.537311 · Cited by 22 · see citing works
Prognostic value of mesothelin expression in patients with triple negative and HER2-positive breast cancers.
Bayoğlu, I., Kucukzeybek, B., Kucukzeybek, Y., Varol, U., Yıldız, I., Alacacıoğlu, A., Akyol, M., Demir, L., Dirican, A., Yildiz, Y., et al. (2015) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2015.01.019 · Cited by 22
Mesothelial cells regulate immune responses in health and disease: role for immunotherapy in malignant mesothelioma.
Mutsaers, S., Pixley, F., Prêle, C., & Hoyne, G. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.04.005 · Cited by 21 · see citing works
Unique cellular interactions between pancreatic cancer cells and the omentum
Feygenzon, V., Loewenstein, S., Lubezky, N., Pasmanic-Chor, M., Sher, O., Klausner, J., & Lahat, G. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179862 · Cited by 21 · see citing works
Application of CAR-T cell therapy targeting mesothelin in solid tumor treatment
Chen, Q., Sun, Y., & Li, H. (2024) · Discover Oncology · doi:10.1007/s12672-024-01159-x · Cited by 17 · see citing works
“Cell survival and proliferation are promoted through a novel auto/paracrine interleukin-6/ soluble IL-6 receptor (IL-6/sIL-6R) trans-signaling pathway [54].”
Background
Contributory role of microRNAs in anti‐cancer effects of small molecule inhibitor of telomerase (BIBR1532) on acute promyelocytic leukemia cell line
Pourbagheri-Sigaroodi, A., Bashash, D., Safaroghli-azar, A., Farshi‐Paraasghari, M., Momeny, M., Mansoor, F. N., & Ghaffari, S. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.01.018 · Cited by 20
Advancing pancreatic cancer therapy by mesothelin-specific nanobody conjugation
Yi, S., Noh, K., Kim, H., Jung, E., Kim, S., Lee, J., Guk, K., Choi, J., Lim, E.-K., Kim, S., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02325-7 · Cited by 19 · see citing works
Targeting mesothelin-CD24 axis repolarizes tumor-associated macrophages to potentiate PD-1 blockade therapy in high-grade serous ovarian cancer
Zhong, Y., Wang, Y., Wang, C.-Y., Cao, K., Wang, X.-L., Xu, X.-Y., Yang, M.-R., Zhang, G.-D., Liu, H.-O., & Lu, J.-Q. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-011230 · Cited by 19 · see citing works
“12 Consistent with previous findings, we used proliferation assays to demonstrate that knockdown Msln significantly impaired tumor cell proliferation in murine ovarian cancer cell lines (online supplemental figure 8A–”
MSLN induced EMT, cancer stem cell traits and chemotherapy resistance of pancreatic cancer cells
Hu, J., Wang, J., Guo, X., Fan, Q., Li, X.-M., Li, K., Wang, Z., Liang, S., Amin, B., Zhang, N.-W., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29210 · Cited by 19 · see citing works
Self-citation
Targeting Mesothelin in Solid Tumours: Anti-mesothelin Antibody and Drug Conjugates
Chu, Q. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01367-8 · Cited by 19
Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks
Pandey, S. K., Machlof-Cohen, R., Santhanam, M., Shteinfer‐Kuzmine, A., & Shoshan‐Barmatz, V. (2022) · Biomolecules · doi:10.3390/biom12070895 · Cited by 22 · see citing works
“The overexpression of MSLN activates multiple intracellular pathways, including nuclear factor-kappaB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinases (PI3K) pathways, with the consequent promotion of cell proliferation, migration, and metastasis to distal sites and the inhibition of ap…”
Background
Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma
Li, T., Li, H., Li, S., Xu, S., Zhang, W., Gao, H., Xu, H.-X., Wu, C.-T., Wang, W., Yu, X.-J., et al. (2019) · Cancer Medicine · doi:10.1002/cam4.2430 · Cited by 17 · see citing works
Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer
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BackgroundInfluential
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“Further, MSLN prevents the drug-induced release of pro-apoptotic TNF-a by activating Akt/PI3K pathway, enhances the expression of antiapoptotic genes such as Bcl-2 and Mcl-1, and inhibits the expression of pro-apoptotic factors such as Bad and Bax [42].”
Background

Authors: Bharadwaj, U., Marin-Muller, C., Li, M., Chen, C., & Yao, Q.
Affiliations: Baylor College of Medicine (US)
Corresponding author: Yao, Qizhi
ORCID: Bharadwaj, Uddalak
Li, Min
Chen, Changyi
Yao, Qizhi
Venue: Molecular Cancer
Publisher: Springer Science and Business Media LLC
Published: 2011-08-31
Volume: 10
Issue: 1
Pages: 106-106
ISSN: 1476-4598 (ISSN-L)
DOI: 10.1186/1476-4598-10-106
PMC: PMC3175472
OpenAlex: W2102073127
Cited by: 151
References: 55
Citations by year: 2026: 9 · 2025: 19 · 2024: 13 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 17 · 2019: 14 · 2018: 6 · 2017: 10 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 6 · 2012: 10
FWCI: 3.31
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Molecular Cancer (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: National Institutes of Health
National Cancer Institute (CA140828, R21CA140828)
Topics: Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: mesothelin, pancreatic cancer, TNF-α, apoptosis resistance, interleukin-6, Mcl-1, Bcl-xL, Bad phosphorylation, cell cycle progression, cyclin A, caspase activation, gemcitabine, chemosensitization, tumor microenvironment
MeSH terms: Phosphoinositide-3 Kinase Inhibitors, Mesothelin, Antineoplastic Agents, Cell Survival, Chromones, Coumarins, Enzyme Activation, Humans, Morpholines, Pancreatic Neoplasms, Recombinant Proteins, Tumor Necrosis Factor-alpha, Interleukin-6, Gene Expression, S Phase, NF-kappa B, Apoptosis, Genes, Reporter, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-bcl-2, Phosphatidylinositol 3-Kinases, Cyclin A, Protein Transport, RNA Interference, Cell Line, Tumor, Luciferases, Renilla, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, I-kappa B Kinase, Caspase 3, Gene Knockdown Techniques, GPI-Linked Proteins, Myeloid Cell Leukemia Sequence 1 Protein

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Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression

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