Abstract
BackgroundChemotherapeutic 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.MethodsWe 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.ResultsHere, 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.ConclusionOverall, 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.
Highlights
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
Microtubule associated serine threonine like kinase (MASTL) is markedly upregulated in colorectal cancer To characterize the potential role of MASTL in colon carcinogenesis, we first assessed its expression in a high through-put transcriptome analysis of a large patient cohort
We found a similar significant increase in MASTL expression in all stages of colon cancer compared to normal samples, analyzing the the cancer genomic atlas (TCGA) database (Fig. 1b)
Summary
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. Cell cycle kinases play a key role in promoting cell cycle progression through its different phases Among these kinases, MASTL (named Greatwall in Xenopus and Drosophila) was identified recently and is demonstrated to be important for mitosis, especially the G2/M checkpoint. A causal role for MASTL in resistance against anti-cancer therapies has been demonstrated using cell lines derived from initial and recurrent tumors of head and neck squamous cell carcinoma [3]. These studies suggest a critical role for MASTL in oncogenic growth and tumorigenesis. A causal association of MASTL in regulating colon cancer growth and progression and its potential role in resistance to conventional therapy, a critical factor in unrelenting patient death, remains an area of active investigation
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