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NCTD Elicits Proapoptotic and Antiglycolytic Effects on Colorectal Cancer Cells Via Modulation of Fam46c Expression and Inhibition of ERK1/2 Signaling

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NCTD Elicits Proapoptotic and Antiglycolytic Effects on Colorectal Cancer Cells Via Modulation of Fam46c Expression and Inhibition of ERK1/2 Signaling 774 MOLECULAR MEDICINE REPORTS 22: 774-782, 2020 NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling SHIQIANG ZHANG1,2*, YUN YANG1,2*, YUNWEI HUA3, CHEN HU4 and YI ZHONG2 1Shanghai University of Traditional Chinese Medicine; Departments of 2Oncology and 3Gastroenterology, Shanghai Traditional Chinese Medicine-Integrated Hospital; 4School of Life Sciences and Technology, Tongji University, Shanghai 200082, P.R. China Received April 18, 2019; Accepted November 1, 2019 DOI: 10.3892/mmr.2020.11151 Abstract. Colorectal cancer is a digestive tract malignancy identified a novel therapeutic target of NCTD in the clinical and the third leading cause of cancer-related mortality treatment of colorectal cancer. worldwide. Norcantharidin (NCTD), the demethylated form of cantharidin, has been reported to possess anticancer Introduction properties. Family-with-sequence-similarity-46c (Fam46c), a non-canonical poly(A) polymerase, has been reported to Colorectal cancer was the third leading cause of cancer-related be critical in NCTD‑mediated effects in numerous types of deaths worldwide in 2016 (1,2). Its pathogenesis is closely cancer, including hepatoma. In the current study, it was found related to various factors, including lifestyle, heredity and that Fam46c expression was reduced in colorectal cancer colorectal adenoma (3,4). Colorectal cancer often arises at tissues and cells. Treatment with NCTD was observed to the age of 40-50 years, with the ratio of men to women being significantly enhance apoptosis and inhibit glycolysis in 1.65:1 (1). According to previous studies, the incidence of colorectal cancer cells. In addition, Fam46c and cleaved colorectal cancer has been steadily increasing in China over caspase 3 expression levels were found to be increased in the years, especially in underdeveloped areas (5-7). Currently, response to NCTD treatment, in contrast to tumor‑specific the main treatment for colorectal cancer is surgery, accom- pyruvate kinase M2 and phosphorylated ERK expression, panied with chemotherapy, immunotherapy and traditional which was reduced. Importantly, overexpression of Fam46c Chinese medicine (8-10). However, due to high rates of recur- exerted similar effects as NCTD treatment on the apoptosis rence and metastasis, colorectal cancer remains a burden for and glycolysis of colorectal cancer cells, whereas Fam46c patients (1,2). Studies have revealed that cancer cells, including knockdown strongly attenuated the effect of NCTD. Moreover, colorectal cancer cells, take up high amounts of glucose and epidermal growth factor, which acts as an agonist of ERK1/2 rely on glycolysis for ATP generation (11,12). Efficient conver- signaling, weakened the effects of NCTD on colorectal sion of glucose into macromolecules is necessary for a number cancer cells. Taken together, the results indicated that NCTD of cellular processes, including cell growth and glycolysis (13). promotes apoptosis and suppresses glycolysis in colorectal Indeed, cancer cells require high glucose consumption and cancer cells by possibly targeting Fam46c and inhibiting lactate production to sustain their proliferation (11,12,14,15). ERK1/2 signaling, hence suggesting that Fam46c may act as a Norcantharidin (NCTD) is the demethylated form of tumor suppressor in colorectal cancer. Thus, the present study cantharidin, an active ingredient of a traditional medicine, blister beetle, which possesses antitumor properties (16). It is reported that NCTD is easier to synthesize and less toxic than cantharidin, and displays anticancer activity (17-20). NCTD has been found to be involved in suppressing proliferation and inducing apoptosis in a variety of cancer types, including Correspondence to: Dr Yi Zhong, Department of Oncology, colorectal cancer, hepatoma and breast cancer (21-24). Shanghai Traditional Chinese Medicine‑Integrated Hospital, Moreover, NCTD has been found to suppress cancer cell 230 Baoding Road, Hongkou, Shanghai 200082, P.R. China E‑mail: [email protected] invasion by reducing expression of matrix metalloproteinase-2 and -9 and adhesion molecules, such as E‑cadherin and integrin *Contributed equally in CT26 colon cancer cells (25,26). NCTD is also capable of inhibiting epithelial-mesenchymal transition (EMT) in colon Key words: family-with-sequence-similarity-46c, norcantharidin, cancer cells (27), which contributes to the complex patho- proapoptosis, glycolysis, ERK1/2 signaling genesis of tumors and fibrosis (28,29). Additionally, studies have revealed that members of the mitogen-activated protein kinase (MAPK) family, including p38MAPK, extracellular ZHANG et al: PROAPOPTOTIC AND ANTIGLYCOLYTIC EFFECTS OF NCTD ON COLORECTAL CANCER CELLS 775 signal-regulated kinase (ERK) and c-Jun N‑terminal kinase Construction of the lentivirus. Short hairpin (sh)RNA (JNK), are involved in NCTD‑induced cell apoptosis in sequences targeting three different sites of the Fam46c gene glioma, colon and breast cancers (18,20,23). (NM_017709.3) were synthesized (Table I), and three shRNA Family-with-sequence-similarity-46c (Fam46c) is a constructs were formed by double-strand annealing. In addi- non-canonical poly(A) polymerase that belongs to the Fam46 tion, the coding DNA sequence (CDS) region of Fam46c superfamily of nucleotidyltransferases, along with three other with a length of 1,176 bp was also synthesized (Genewiz, types of Fam46 proteins (Fam46a, b and d). Studies have Inc.). Subsequently, 1 µg/µl shRNA constructs and the CDS identified that short progression‑free survival and decreased region were respectively inserted into the AgelI/EcolI restric- overall survival of multiple myeloma cases are associated tion sites of the pLKO.1-puro vector (Addgene, Inc.) and the with deletions of Fam46c, and Fam46c loss may promote cell EcoRI/BamHI sites of the pLVX-Puro vector (Addgene, Inc.). survival in myeloma (30-32). Therefore, Fam46c potentially Following DNA sequencing (Shanghai Meiji Biomedical acts as a tumor suppressor in multiple myeloma (33). Fam46c Technology Co., Ltd.), 1,000 ng pLKO.1-shFam46c or is also closely related to the anticancer effects of NCTD in 1,000 ng pLVX-Puro-Fam46c was co-transfected into 293T hepatoma and knockdown of Fam46c may partially attenuate cells (American Type Culture Collection) with viral packaging the antimetastatic effects of NCTD on hepatoma (34,35). plasmids psPAX2 (100 ng) and pMD2G (900 ng) (Addgene, However, whether Fam46c is involved in the apoptotic and Inc.) using Lipofectamine® 2000 (Invitrogen; Thermo Fisher glycolytic effects of NCTD in colorectal cancer remains Scientific, Inc.), and then the cells were cultured in DMEM largely unknown. (HyClone; GE Healthcare Life Sciences), supplemented Herein, it was found that Fam46c expression was notably with 10% FBS (Gibco; Thermo Fisher Scientific, Inc.), and reduced in colorectal cancer tissues and cells. NCTD treatment maintained in a humidified atmosphere of 37˚C and 5% CO2. significantly induced cell apoptosis and glycolysis, which was Virus particles were collected by ultracentrifugation (4˚C; accompanied with changes in related-genes, and was potently 72,000 x g; 2 h) 48 h after transfection. counteracted by Fam46c downregulation. Overall, this suggested the potential role of Fam46c as a tumor suppressor Experimental grouping. A total of 5x104 HT29, LOVO or in colorectal cancer. SW620 cells were infected with Fam46c overexpression (Fam46c)/vector or Fam46c interference (shFam46c)/nega- Materials and methods tive control (shNC) lentiviruses (MOI=10), while RPMI‑1640 medium-treated cells were used as controls. Efficiency of Patient samples. After obtaining written informed consent Fam46c overexpression or knockdown was verified via reverse from patients with colorectal cancer who were treated at the transcription-quantitative PCR (RT-qPCR) and western blot- Shanghai Traditional Chinese Medicine‑Integrated Hospital, ting after 48 h of infection. five paired tumor and paracancer tissues were collected from HT29 and LOVO cells were divided and treated as follows: five patients (age, 18‑75 years; sex, 2 females and 3 males) Vehicle, 5 µg/ml NCTD (cat. no. 29745-04-8; Shanghai Aladdin between March 2018 and June 2018, and immediately frozen Bio‑Chem Technology Co., Ltd.), 10 µg/ml NCTD, Fam46c in liquid nitrogen at ‑196˚C. The inclusion criteria was as or control lentivirus, vehicle + shNC, vehicle + shFam46c, follows: 1) Patients must comply with the diagnostic criteria in 10 µg/ml NCTD + shNC, and 10 µg/ml NCTD + shFam46c. the ‘Guidelines for the Diagnosis and Treatment of Colorectal Subsequently, cell apoptosis, glucose consumption and Malignancies’ prepared by the Medical Department of the lactate production were examined, and protein-related levels People's Republic of China, and must be clearly diagnosed were determined. Further, HT29 cells were treated with as a colorectal malignant tumor and 2) the patient must not vehicle + vehicle, vehicle + 10 µg/ml NCTD, 10 µg/ml EGF have received medication 7 days prior to the specimen being (R&D Systems, Inc.; solvent, PBS) + vehicle, and 10 µg/ml obtained. The exclusion criteria included that the specimen EGF + 10 µg/ml NCTD. Next, glucose consumption, lactate could not be contaminated or destroyed. Immunochemistry production and protein-related levels were determined. The detection was performed to analyze the expression of Fam46c concentrations of NCTD (5 and 10 µg/ml) were determined in these tissues. The experiments
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