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MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/β-catenin signaling.
Mol Cancer. 2018 08 01; 17(1):111.MC

Abstract

BACKGROUND

Chemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood.

METHODS

We utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer.

RESULTS

Here, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression.

CONCLUSION

Overall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA.Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program at MSKCC, New York, NY, USA.Division of Biostatistics, University of Miami Miller School of Medicine, Miami, FL, USA.Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program at MSKCC, New York, NY, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA. Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA. Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68022, USA. punita.dhawan@unmc.edu. Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. punita.dhawan@unmc.edu. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. punita.dhawan@unmc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30068336

Citation

Uppada, Srijayaprakash Babu, et al. "MASTL Induces Colon Cancer Progression and Chemoresistance By Promoting Wnt/β-catenin Signaling." Molecular Cancer, vol. 17, no. 1, 2018, p. 111.
Uppada SB, Gowrikumar S, Ahmad R, et al. MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/β-catenin signaling. Mol Cancer. 2018;17(1):111.
Uppada, S. B., Gowrikumar, S., Ahmad, R., Kumar, B., Szeglin, B., Chen, X., Smith, J. J., Batra, S. K., Singh, A. B., & Dhawan, P. (2018). MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/β-catenin signaling. Molecular Cancer, 17(1), 111. https://doi.org/10.1186/s12943-018-0848-3
Uppada SB, et al. MASTL Induces Colon Cancer Progression and Chemoresistance By Promoting Wnt/β-catenin Signaling. Mol Cancer. 2018 08 1;17(1):111. PubMed PMID: 30068336.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/β-catenin signaling. AU - Uppada,Srijayaprakash Babu, AU - Gowrikumar,Saiprasad, AU - Ahmad,Rizwan, AU - Kumar,Balawant, AU - Szeglin,Bryan, AU - Chen,Xi, AU - Smith,J Joshua, AU - Batra,Surinder K, AU - Singh,Amar B, AU - Dhawan,Punita, Y1 - 2018/08/01/ PY - 2017/12/11/received PY - 2018/06/29/accepted PY - 2018/8/3/entrez PY - 2018/8/3/pubmed PY - 2019/3/23/medline KW - Colon cancer KW - Wnt signaling and MASTL SP - 111 EP - 111 JF - Molecular cancer JO - Mol. Cancer VL - 17 IS - 1 N2 - BACKGROUND: Chemotherapeutic agents that modulate cell cycle checkpoints and/or tumor-specific pathways have shown immense promise in preclinical and clinical studies aimed at anti-cancer therapy. MASTL (Greatwall in Xenopus and Drosophila), a serine/threonine kinase controls the final G2/M checkpoint and prevents premature entry of cells into mitosis. Recent studies suggest that MASTL expression is highly upregulated in cancer and confers resistance against chemotherapy. However, the role and mechanism/s of MASTL mediated regulation of tumorigenesis remains poorly understood. METHODS: We utilized a large patient cohort and mouse models of colon cancer as well as colon cancer cells to determine the role of Mastl and associated mechanism in colon cancer. RESULTS: Here, we show that MASTL expression increases in colon cancer across all cancer stages compared with normal colon tissue (P < 0.001). Also, increased levels of MASTL associated with high-risk of the disease and poor prognosis. Further, the shRNA silencing of MASTL expression in colon cancer cells induced cell cycle arrest and apoptosis in vitro and inhibited xenograft-tumor growth in vivo. Mechanistic analysis revealed that MASTL expression facilitates colon cancer progression by promoting the β-catenin/Wnt signaling, the key signaling pathway implicated in colon carcinogenesis, and up-regulating anti-apoptotic proteins, Bcl-xL and Survivin. Further studies where colorectal cancer (CRC) cells were subjected to 5-fluorouracil (5FU) treatment revealed a sharp increase in MASTL expression upon chemotherapy, along with increases in Bcl-xL and Survivin expression. Most notably, inhibition of MASTL in these cells induced chemosensitivity to 5FU with downregulation of Survivin and Bcl-xL expression. CONCLUSION: Overall, our data shed light on the heretofore-undescribed mechanistic role of MASTL in key oncogenic signaling pathway/s to regulate colon cancer progression and chemo-resistance that would tremendously help to overcome drug resistance in colon cancer treatment. SN - 1476-4598 UR - https://www.unboundmedicine.com/medline/citation/30068336/MASTL_induces_Colon_Cancer_progression_and_Chemoresistance_by_promoting_Wnt/β_catenin_signaling_ L2 - https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-018-0848-3 DB - PRIME DP - Unbound Medicine ER -