NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling Retraction in /10.3892/mmr.2023.13078

Zhang,Shiqiang; Yang,Yun; Hua,Yunwei; Hu,Chen; Zhong,Yi

doi:10.3892/mmr.2020.11151

NCTD elicits proapoptotic and antiglycolytic effects on colorectal cancer cells via modulation of Fam46c expression and inhibition of ERK1/2 signaling

Retraction in: /10.3892/mmr.2023.13078

Authors:
- Shiqiang Zhang
- Yun Yang
- Yunwei Hua
- Chen Hu
- Yi Zhong
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Affiliations: Shanghai University of Traditional Chinese Medicine, Shanghai 200082, P.R. China, Department of Gastroenterology, Shanghai Traditional Chinese Medicine‑Integrated Hospital, Shanghai 200082, P.R. China , School of Life Sciences and Technology, Tongji University, Shanghai 200082, P.R. China, Department of Oncology, Shanghai Traditional Chinese Medicine‑Integrated Hospital, Shanghai 200082, P.R. China
Published online on: May 18, 2020 https://doi.org/10.3892/mmr.2020.11151
Pages: 774-782
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer is a digestive tract malignancy and the third leading cause of cancer‑related mortality worldwide. Norcantharidin (NCTD), the demethylated form of cantharidin, has been reported to possess anticancer properties. Family‑with‑sequence‑similarity‑46c (Fam46c), a non‑canonical poly(A) polymerase, has been reported to be critical in NCTD‑mediated effects in numerous types of cancer, including hepatoma. In the current study, it was found that Fam46c expression was reduced in colorectal cancer tissues and cells. Treatment with NCTD was observed to significantly enhance apoptosis and inhibit glycolysis in colorectal cancer cells. In addition, Fam46c and cleaved caspase 3 expression levels were found to be increased in response to NCTD treatment, in contrast to tumor‑specific pyruvate kinase M2 and phosphorylated ERK expression, which was reduced. Importantly, overexpression of Fam46c exerted similar effects as NCTD treatment on the apoptosis and glycolysis of colorectal cancer cells, whereas Fam46c knockdown strongly attenuated the effect of NCTD. Moreover, epidermal growth factor, which acts as an agonist of ERK1/2 signaling, weakened the effects of NCTD on colorectal cancer cells. Taken together, the results indicated that NCTD promotes apoptosis and suppresses glycolysis in colorectal cancer cells by possibly targeting Fam46c and inhibiting ERK1/2 signaling, hence suggesting that Fam46c may act as a tumor suppressor in colorectal cancer. Thus, the present study identified a novel therapeutic target of NCTD in the clinical treatment of colorectal cancer.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Ung L, Lam AY, Morris D and Chua T: Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: A review. Clin Transl Oncol. 16:425–435. 2014. View Article : Google Scholar : PubMed/NCBI
3	Bardhan K and Liu K: Epigenetics and colorectal cancer pathogenesis. Cancers (Basel). 5:676–713. 2013. View Article : Google Scholar : PubMed/NCBI
4	Zoratto F, Rossi L, Verrico M, Papa A, Basso E, Zullo A, Tomao L, Romiti A, Lo Russo G and Tomao S: Focus on genetic and epigenetic events of colorectal cancer pathogenesis: Implications for molecular diagnosis. Tumor Biol. 35:6195–6206. 2014. View Article : Google Scholar
5	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
6	Liu S, Zheng R, Zhang M, Zhang S, Sun X and Chen W: Incidence and mortality of colorectal cancer in China, 2011. Chin J Cancer Res. 27:22–28. 2015.PubMed/NCBI
7	Chen W, Zheng R, Zeng H, Zhang S and He J: Annual report on status of cancer in China, 2011. Chin J Cancer Res. 27:2–12. 2015. View Article : Google Scholar : PubMed/NCBI
8	Sostres C, Gargallo CJ and Lanas A: Aspirin, cyclooxygenase inhibition and colorectal cancer. World J Gastrointest Pharmacol Ther. 5:40–49. 2014. View Article : Google Scholar : PubMed/NCBI
9	Lacy AM, García-Valdecasas JC, Delgado S, Castells A, Taurá P, Piqué JM and Visa J: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: A randomised trial. Lancet. 359:2224–2229. 2002. View Article : Google Scholar : PubMed/NCBI
10	André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F and de Gramont A: Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 27:3109–3116. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wang J, Wang H, Liu A, Fang C, Hao J and Wang Z: Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. Oncotarget. 6:19456–19468. 2015. View Article : Google Scholar : PubMed/NCBI
12	Xu X, Li J, Sun X, Guo Y, Chu D, Wei L, Li X, Yang G, Liu X, Yao L, et al: Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression. Oncotarget. 6:26161–26176. 2015. View Article : Google Scholar : PubMed/NCBI
13	Donnelly RP and Finlay DK: Glucose, glycolysis and lymphocyte responses. Mol Immunol. 68:513–519. 2015. View Article : Google Scholar : PubMed/NCBI
14	Ha TK, Her NG, Lee MG, Ryu BK, Lee JH, Han J, Jeong SI, Kang MJ, Kim NH, Kim HJ and Chi SG: Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. Cancer Res. 72:4097–4109. 2012. View Article : Google Scholar : PubMed/NCBI
15	Chaneton B and Gottlieb E: Rocking cell metabolism: Revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci. 37:309–316. 2012. View Article : Google Scholar : PubMed/NCBI
16	Efferth T, Rauh R, Kahl S, Tomicic M, Böchzelt H, Tome ME, Briehl MM, Bauer R and Kaina B: Molecular modes of action of cantharidin in tumor cells. Biochem Pharmacol. 69:811–818. 2005. View Article : Google Scholar : PubMed/NCBI
17	Yang EB, Tang WY, Zhang K, Cheng LY and Mack PO: Norcantharidin inhibits growth of human HepG2 cell-transplanted tumor in nude mice and prolongs host survival. Cancer Lett. 117:93–98. 1997. View Article : Google Scholar : PubMed/NCBI
18	Yang PY, Chen MF, Kao YH, Hu DN, Chang FR and Wu YC: Norcantharidin induces apoptosis of breast cancer cells: Involvement of activities of mitogen activated protein kinases and signal transducers and activators of transcription. Toxicol In Vitro. 25:699–707. 2011. View Article : Google Scholar : PubMed/NCBI
19	Yeh CB, Hsieh MJ, Hsieh YH, Chien MH, Chiou HL and Yang SF: Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-kB activity. PLoS One. 7:e310552012. View Article : Google Scholar : PubMed/NCBI
20	Zheng J, Du W, Song LJ, Zhang R, Sun LG, Chen FG and Wei XT: Norcantharidin induces growth inhibition and apoptosis of glioma cells by blocking the Raf/MEK/ERK pathway. World J Surg Oncol. 12:2072014. View Article : Google Scholar : PubMed/NCBI
21	Chen YJ, Kuo CD, Tsai YM, Yu CC, Wang GS and Liao HF: Norcantharidin induces anoikis through Jun-N-terminal kinase activation in CT26 colorectal cancer cells. Anticancer Drugs. 19:55–64. 2008. View Article : Google Scholar : PubMed/NCBI
22	Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF and Hsu SL: Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer. 100:158–165. 2002. View Article : Google Scholar : PubMed/NCBI
23	Peng C, Liu X, Liu E, Xu K, Niu W, Chen R, Wang J, Zhang Z, Lin P, Wang J, et al: Norcantharidin induces HT-29 colon cancer cell apoptosis through the alphavbeta6-extracellular signal-related kinase signaling pathway. Cancer Sci. 100:2302–2308. 2009. View Article : Google Scholar : PubMed/NCBI
24	Huang Y, Liu Q, Liu K, Yagasaki K and Zhang G: Suppression of growth of highly-metastatic human breast cancer cells by norcantharidin and its mechanisms of action. Cytotechnology. 59:201–208. 2009. View Article : Google Scholar : PubMed/NCBI
25	Chen YJ, Shieh CJ, Tsai TH, Kuo CD, Ho LT, Liu TY and Liao HF: Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells. Anticancer Drugs. 16:293–299. 2005. View Article : Google Scholar : PubMed/NCBI
26	Chen YJ, Chang WM, Liu YW, Lee CY, Jang YH, Kuo CD and Liao HF: A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells. Chem Biol Interact. 181:440–446. 2009. View Article : Google Scholar : PubMed/NCBI
27	Peng C, Li Z, Niu Z, Niu W, Xu Z, Gao H, Niu W, Wang J, He Z, Gao C, et al: Norcantharidin suppresses colon cancer cell epithelial-mesenchymal transition by inhibiting the αvβ6-ERK-Ets1 signaling pathway. Sci Rep. 6:205002016. View Article : Google Scholar : PubMed/NCBI
28	Radisky DC, Kenny PA and Bissell MJ: Fibrosis and cancer: Do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 101:830–839. 2007. View Article : Google Scholar : PubMed/NCBI
29	Xia J, He LQ and Su X: Interventional mechanisms of herbs or herbal extracts on renal interstitial fibrosis. J Integr Med. 14:165–173. 2016. View Article : Google Scholar : PubMed/NCBI
30	Boyd KD, Ross FM, Walker BA, Wardell CP, Tapper WJ, Chiecchio L, Dagrada G, Konn ZJ, Gregory WM, Jackson GH, et al: Mapping of chromosome 1p deletions in myeloma identifies FAM46C at 1p12 and CDKN2C at 1p32. 3 as being genes in regions associated with adverse survival. Clin Cancer Res. 17:7776–7784. 2011. View Article : Google Scholar : PubMed/NCBI
31	Prideaux SM, Conway O'Brien E and Chevassut TJ: The genetic architecture of multiple myeloma. Adv Hematol. 2014:8640582014. View Article : Google Scholar : PubMed/NCBI
32	Zhu YX, Shi CX, Bruins LA, Jedlowski P, Wang X, Kortüm KM, Luo M, Ahmann JM, Braggio E and Stewart AK: Loss of FAM46C promotes cell survival in myeloma. Cancer Res. 77:4317–4327. 2017. View Article : Google Scholar : PubMed/NCBI
33	Mroczek S, Chlebowska J, Kuliński TM, Gewartowska O, Gruchota J, Cysewski D, Liudkovska V, Borsuk E, Nowis D and Dziembowski A: The non-canonical poly (A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma. Nat Commun. 8:6192017. View Article : Google Scholar : PubMed/NCBI
34	Zhang QY, Yue XQ, Jiang YP, Han T and Xin HL: FAM46C is critical for the anti-proliferation and pro-apoptotic effects of norcantharidin in hepatocellular carcinoma cells. Sci Rep. 7:3962017. View Article : Google Scholar : PubMed/NCBI
35	Wan XY, Zhai XF, Jiang YP, Han T, Zhang QY and Xin HL: Antimetastatic effects of norcantharidin on hepatocellular carcinoma cells by up-regulating FAM46C expression. Am J Transl Res. 9:155–166. 2017.PubMed/NCBI
36	Peng F, Wei YQ, Tian L, Yang L, Zhao X, Lu Y, Mao YQ, Kan B, Lei S, Wang GS, et al: Induction of apoptosis by norcantharidin in human colorectal carcinoma cell lines: Involvement of the CD95 receptor/ligand. J Cancer Res Clin Oncol. 128:223–230. 2002. View Article : Google Scholar : PubMed/NCBI
37	Chang C, Zhu YQ, Mei JJ, Liu SQ and Luo J: Involvement of mitochondrial pathway in NCTD-induced cytotoxicity in human hepG2 cells. J Exp Clin Cancer Res. 29:1452010. View Article : Google Scholar : PubMed/NCBI
38	Liu D, Shi P, Yin X, Chen Z and Zhang X: Effect of norcantharidin on the human breast cancer Bcap-37 cells. Connect Tissue Res. 53:508–512. 2012. View Article : Google Scholar : PubMed/NCBI
39	Hong J, Kang B, Kim A, Hwang S, Ahn J, Lee S, Kim J, Park JH and Cheon DS: Development of a highly sensitive real-time one step RT-PCR combined complementary locked primer technology and conjugated minor groove binder probe. Virol J. 8:3302011. View Article : Google Scholar : PubMed/NCBI
40	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
41	Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI
42	Liang J, Cao R, Zhang Y, Xia Y, Zheng Y, Li X, Wang L, Yang W and Lu Z: PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nat Commun. 7:124312016. View Article : Google Scholar : PubMed/NCBI
43	Etokebe GE, Zienolddiny S, Kupanovac Z, Enersen M, Balen S, Flego V, Bulat-Kardum L, Radojčić-Badovinac A, Skaug V, Bakke P, et al: Association of the FAM46A gene VNTRs and BAG6 rs3117582 SNP with non small cell lung cancer (NSCLC) in Croatian and Norwegian populations. PLoS One. 10:e01226512015. View Article : Google Scholar : PubMed/NCBI
44	Kang HC, Kim IJ, Park JH, Shin Y, Ku JL, Jung MS, Yoo BC, Kim HK and Park JG: Identification of genes with differential expression in acquired drug-resistant gastric cancer cells using high-density oligonucleotide microarrays. Clin Cancer Res. 10:272–284. 2004. View Article : Google Scholar : PubMed/NCBI
45	Liang T, Ye X, Liu Y, Qiu X, Li Z, Tian B and Yan D: FAM46B inhibits cell proliferation and cell cycle progression in prostate cancer through ubiquitination of β-catenin. Exp Mol Med. 50:1–12. 2018. View Article : Google Scholar : PubMed/NCBI
46	Tanaka H, Kanda M, Shimizu D, Tanaka C, Kobayashi D, Hayashi M, Iwata N, Yamada S, Fujii T, Nakayama G, et al: FAM46C serves as a predictor of hepatic recurrence in patients with resectable gastric cancer. Ann Surg Oncol. 24:3438–3445. 2017. View Article : Google Scholar : PubMed/NCBI
47	Kok SH, Cheng SJ, Hong CY, Lee JJ, Lin SK, Kuo YS, Chiang CP and Kuo MY: Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. Cancer Lett. 217:43–52. 2005. View Article : Google Scholar : PubMed/NCBI
48	Luan J, Duan H, Liu Q, Yagasaki K and Zhang G: Inhibitory effects of norcantharidin against human lung cancer cell growth and migration. Cytotechnology. 62:349–355. 2010. View Article : Google Scholar : PubMed/NCBI
49	Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC and Lu Z: ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol. 14:1295–1304. 2012. View Article : Google Scholar : PubMed/NCBI
50	Yang W and Lu Z: Nuclear PKM2 regulates the Warburg effect. Cell Cycle. 12:3154–3158. 2013. View Article : Google Scholar : PubMed/NCBI
51	Diener S, Bayer S, Sabrautzki S, Wieland T, Mentrup B, Przemeck GK, Rathkolb B, Graf E, Hans W, Fuchs H, et al: Exome sequencing identifies a nonsense mutation in Fam46a associated with bone abnormalities in a new mouse model for skeletal dysplasia. Mamm Genome. 27:111–121. 2016. View Article : Google Scholar : PubMed/NCBI