Galectin‑3 blockade suppresses the growth of cetuximab‑resistant human oral squamous cell carcinoma

Yin,Peng; Cui,Shuanlong; Liao,Xiangling; Yao,Xiaoguang

doi:10.3892/mmr.2021.12325

Galectin‑3 blockade suppresses the growth of cetuximab‑resistant human oral squamous cell carcinoma

Authors:
- Peng Yin
- Shuanlong Cui
- Xiangling Liao
- Xiaoguang Yao
View Affiliations

Affiliations: Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing 110112, P.R. China, Department of Stomatology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China, Department of Surgery, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China
Published online on: July 29, 2021 https://doi.org/10.3892/mmr.2021.12325
Article Number: 685
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Oral squamous cell carcinoma (OSCC) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with OSCC due to unknown mechanisms. Galectin‑3 (Gal‑3) is a β‑galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal‑3 in cetuximab‑resistant (cet‑R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal‑3 inhibitor was used to treat cet‑R tumors, and the tumor volume was monitored. The expression of Gal‑3, phosphorylated (p)‑ERK1/2 and p‑Akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal‑3 inhibitor on HSC3 tumor xenografts was also investigated. HSC3 cells were cultured in vitro to investigate the regulatory effects of Gal‑3 on ERK1/2 and Akt via western blotting. In addition, the effects of the Gal‑3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSC3 cells were investigated by performing Cell Counting Kit‑8, colony formation, Transwell and apoptosis assays, respectively. In cet‑R OSCC tumors, increased expression of Gal‑3, p‑ERK1/2 and p‑Akt was observed. Further research demonstrated that Gal‑3 regulated the expression of both ERK1/2 and Akt in HSC3 cells by promoting phosphorylation. Moreover, the Gal‑3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet‑R HSC3 cells. In addition, the Gal‑3 inhibitor suppressed the growth of cet‑R tumors. Collectively, the results indicated that the Gal‑3 inhibitor and cetuximab displayed a synergistic inhibitory effect on OSCC tumors. In summary, the present study demonstrated that Gal‑3 may serve an important role in cet‑R OSCC. The combination of cetuximab and the Gal‑3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.

View Figures

View References

1	Cancer IAfRo: Global Cancer Observatory Available from. http://www-dep.iarc.fr/2007.
2	Muzaffar J, Bari S, Kirtane K and Chung CH: Recent advances and future directions in clinical management of head and neck squamous cell carcinoma. Cancers (Basel). 13:3382021. View Article : Google Scholar : PubMed/NCBI
3	Prawira A, Brana-Garcia I, Spreafico A, Hope A, Waldron J, Razak AR, Chen EX, Jang R, O'Sullivan B, Giuliani M, et al: Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001). Invest New Drugs. 34:575–583. 2016. View Article : Google Scholar : PubMed/NCBI
4	Yamaoka T, Ohba M and Ohmori T: Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms. Int J Mol Sci. 18:24202017. View Article : Google Scholar : PubMed/NCBI
5	Saba NF, Chen ZG, Haigentz M, Bossi P, Rinaldo A, Rodrigo JP, Mäkitie AA, Takes RP, Strojan P, Vermorken JB and Ferlito A: Targeting the EGFR and immune pathways in squamous cell carcinoma of the head and neck (SCCHN): Forging a new alliance. Mol Cancer Ther. 18:1909–1915. 2019. View Article : Google Scholar : PubMed/NCBI
6	Campbell NP, Hensing TA, Bhayani MK, Shaikh AY and Brockstein BE: Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck. Expert Rev Anticancer Ther. 16:847–858. 2016. View Article : Google Scholar : PubMed/NCBI
7	Vigneswaran N and Williams MD: Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am. 26:123–141. 2014. View Article : Google Scholar : PubMed/NCBI
8	Ohnishi Y, Yasui H, Kakudo K and Nozaki M: Cetuximab-resistant oral squamous cell carcinoma cells become sensitive in anchorage-independent culture conditions through the activation of the EGFR/AKT pathway. Int J Oncol. 47:2165–2172. 2015. View Article : Google Scholar : PubMed/NCBI
9	Rong C, Muller MF, Xiang F, Jensen A, Weichert W, Major G, Plinkert PK, Hess J and Affolter A: Adaptive ERK signalling activation in response to therapy and in silico prognostic evaluation of EGFR-MAPK in HNSCC. Br J Cancer. 123:288–297. 2020. View Article : Google Scholar : PubMed/NCBI
10	Modenutti CP, Capurro JIB, Di Lella S and Marti MA: The structural biology of galectin-ligand recognition: Current advances in modeling tools, protein engineering, and inhibitor design. Front Chem. 7:8232019. View Article : Google Scholar : PubMed/NCBI
11	Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, Bellotti C, Salehi LB and Ricci A: Galectin-3: One molecule for an alphabet of diseases, from A to Z. Int J Mol Sci. 19:3792018. View Article : Google Scholar : PubMed/NCBI
12	Nangia-Makker P, Hogan V and Raz A: Galectin-3 and cancer stemness. Glycobiology. 28:172–181. 2018. View Article : Google Scholar : PubMed/NCBI
13	Diaz-Alvarez L and Ortega E: The many roles of galectin-3, a multifaceted molecule, in innate immune responses against pathogens. Mediators Inflamm. 2017:92475742017. View Article : Google Scholar : PubMed/NCBI
14	Mirandola L, Yu Y, Cannon MJ, Jenkins MR, Rahman RL, Nguyen DD, Grizzi F, Cobos E, Figueroa JA and Chiriva-Internati M: Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer. Gynecol Oncol. 135:573–579. 2014. View Article : Google Scholar : PubMed/NCBI
15	Fukumori T, Kanayama HO and Raz A: The role of galectin-3 in cancer drug resistance. Drug Resist Updat. 10:101–108. 2007. View Article : Google Scholar : PubMed/NCBI
16	Dondoo TO, Fukumori T, Daizumoto K, Fukawa T, Kohzuki M, Kowada M, Kusuhara Y, Mori H, Nakatsuji H, Takahashi M and Kanayama HO: Galectin-3 is implicated in tumor progression and resistance to anti-androgen drug through regulation of androgen receptor signaling in prostate cancer. Anticancer Res. 37:125–134. 2017. View Article : Google Scholar : PubMed/NCBI
17	Weber M, Buttner-Herold M, Distel L, Ries J, Moebius P, Preidl R, Geppert CI, Neukam FW and Wehrhan F: Galectin 3 expression in primary oral squamous cell carcinomas. BMC Cancer. 17:9062017. View Article : Google Scholar : PubMed/NCBI
18	Wang LP, Chen SW, Zhuang SM, Li H and Song M: Galectin-3 accelerates the progression of oral tongue squamous cell carcinoma via a Wnt/β-catenin-dependent pathway. Pathol Oncol Res. 19:461–474. 2013. View Article : Google Scholar : PubMed/NCBI
19	Zhang D, Chen ZG, Liu SH, Dong ZQ, Dalin M, Bao SS, Hu YW and Wei FC: Galectin-3 gene silencing inhibits migration and invasion of human tongue cancer cells in vitro via downregulating β-catenin. Acta Pharmacol Sin. 34:176–184. 2013. View Article : Google Scholar : PubMed/NCBI
20	Ruvolo PP: Galectin 3 as a guardian of the tumor microenvironment. Biochim Biophys Acta. 1863:427–437. 2016. View Article : Google Scholar : PubMed/NCBI
21	Kilkenny C, Browne W, Cuthill IC, Emerson M and Altman DG; NC3Rs Reporting Guidelines Working Group, : Animal research: Reporting in vivo experiments: The ARRIVE guidelines. Br J Pharmacol. 160:1577–1579. 2010. View Article : Google Scholar : PubMed/NCBI
22	Yin J, Jung JE, Choi SI, Kim SS, Oh YT, Kim TH, Choi E, Lee SJ, Kim H, Kim EO, et al: Inhibition of BMP signaling overcomes acquired resistance to cetuximab in oral squamous cell carcinomas. Cancer Lett. 414:181–189. 2018. View Article : Google Scholar : PubMed/NCBI
23	Zhang H, Liu P, Zhang Y, Han L, Hu Z, Cai Z and Cai J: Inhibition of galectin-3 augments the antitumor efficacy of PD-L1 blockade in non-small-cell lung cancer. FEBS Open Bio. 11:911–920. 2021. View Article : Google Scholar : PubMed/NCBI
24	Al Kafri N and Hafizi S: Galectin-3 stimulates tyro3 receptor tyrosine kinase and erk signalling, cell survival and migration in human cancer cells. Biomolecules. 10:10352020. View Article : Google Scholar : PubMed/NCBI
25	Seyed Jafari SM and Hunger RE: IHC optical density score: A new practical method for quantitative immunohistochemistry image analysis. Appl Immunohistochem Mol Morphol. 25:e12–e13. 2017. View Article : Google Scholar : PubMed/NCBI
26	Barbe AM, Berbets AM, Davydenko IS, Koval HD, Yuzko VO and Yuzko OM: Expression and significance of matrix metalloproteinase-2 and matrix metalloproteinas-9 in endometriosis. J Med Life. 13:314–320. 2020.PubMed/NCBI
27	Yu F, Finley RL Jr, Raz A and Kim HR: Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation. J Biol Chem. 277:15819–15827. 2002. View Article : Google Scholar : PubMed/NCBI
28	Li M, Chen YB, Liu F, Qu JQ, Ren LC, Chai J and Tang CE: Galectin3 facilitates the proliferation and migration of nasopharyngeal carcinoma cells via activation of the ERK1/2 and Akt signaling pathways, and is positively correlated with the inflammatory state of nasopharyngeal carcinoma. Mol Med Rep. 23:3702021. View Article : Google Scholar : PubMed/NCBI
29	Al-Salam S, Hashmi S, Jagadeesh GS and Tariq S: Galectin-3: A cardiomyocyte antiapoptotic mediator at 24-hour post myocardial infarction. Cell Physiol Biochem. 54:287–302. 2020. View Article : Google Scholar : PubMed/NCBI
30	Grandis JR and Tweardy DJ: Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 53:3579–3584. 1993.PubMed/NCBI
31	Bei R, Budillon A, Masuelli L, Cereda V, Vitolo D, Di Gennaro E, Ripavecchia V, Palumbo C, Ionna F, Losito S, et al: Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients. J Pathol. 204:317–325. 2004. View Article : Google Scholar : PubMed/NCBI
32	Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F and Salomon DS: Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 366:2–16. 2006. View Article : Google Scholar : PubMed/NCBI
33	Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK and Milas L: Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 62:7350–7356. 2002.PubMed/NCBI
34	Tao Y, Auperin A, Sun X, Sire C, Martin L, Coutte A, Lafond C, Miroir J, Liem X, Rolland F, et al: Avelumab-cetuximab-radiotherapy versus standards of care in locally advanced squamous-cell carcinoma of the head and neck: The safety phase of a randomised phase III trial GORTEC 2017-01 (REACH). Eur J Cancer. 141:21–29. 2020. View Article : Google Scholar : PubMed/NCBI
35	Merlano MC, Denaro N, Vecchio S, Licitra L, Curcio P, Benasso M, Bagicalupo A, Numico G, Russi E, Corvo' R, et al: Phase III randomized study of induction chemotherapy followed by definitive radiotherapy + cetuximab versus chemoradiotherapy in squamous cell carcinoma of head and neck: The INTERCEPTOR-GONO Study (NCT00999700). Oncology. 98:763–770. 2020. View Article : Google Scholar : PubMed/NCBI
36	Gebre-Medhin M, Brun E, Engstrom P, Haugen Cange H, Hammarstedt-Nordenvall L, Reizenstein J, Nyman J, Abel E, Friesland S, Sjödin H, et al: ARTSCAN III: A randomized phase iii study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer. J Clin Oncol. 39:38–47. 2021. View Article : Google Scholar : PubMed/NCBI
37	Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 354:567–578. 2006. View Article : Google Scholar : PubMed/NCBI
38	Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A and Baselga J: Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 25:2171–2177. 2007. View Article : Google Scholar : PubMed/NCBI
39	Bray SM, Lee J, Kim ST, Hur JY, Ebert PJ, Calley JN, Wulur IH, Gopalappa T, Wong SS, Qian HR, et al: Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients. Sci Rep. 9:153652019. View Article : Google Scholar : PubMed/NCBI
40	Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, et al: Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 3:99ra862011. View Article : Google Scholar : PubMed/NCBI
41	Napolitano S, Martini G, Rinaldi B, Martinelli E, Donniacuo M, Berrino L, Vitagliano D, Morgillo F, Barra G, De Palma R, et al: Primary and acquired resistance of colorectal cancer to anti-EGFR monoclonal antibody can be overcome by combined treatment of regorafenib with cetuximab. Clin Cancer Res. 21:2975–2983. 2015. View Article : Google Scholar : PubMed/NCBI
42	Ercan D, Xu C, Yanagita M, Monast CS, Pratilas CA, Montero J, Butaney M, Shimamura T, Sholl L, Ivanova EV, et al: Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2:934–947. 2012. View Article : Google Scholar : PubMed/NCBI
43	Li Y, Zang H, Qian G, Owonikoko TK, Ramalingam SR and Sun SY: ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor-mutant non-small cell lung cancer cells to osimertinib. Cancer. 126:1339–1350. 2020. View Article : Google Scholar : PubMed/NCBI
44	Liu X, Chen X, Shi L, Shan Q, Cao Q, Yue C, Li H, Li S, Wang J, Gao S, et al: The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma. J Exp Clin Cancer Res. 38:2192019. View Article : Google Scholar : PubMed/NCBI
45	Gao L, Xu J, He G, Huang J, Xu W, Qin J, Zheng P, Ji M, Chang W, Ren L, et al: CCR7 high expression leads to cetuximab resistance by cross-talking with EGFR pathway in PI3K/AKT signals in colorectal cancer. Am J Cancer Res. 9:2531–2543. 2019.PubMed/NCBI
46	Han Y, Peng Y, Fu Y, Cai C, Guo C, Liu S, Li Y, Chen Y, Shen E, Long K, et al: MLH1 deficiency induces cetuximab resistance in colon cancer via Her-2/PI3K/AKT signaling. Adv Sci (Weinh). 7:20001122020. View Article : Google Scholar : PubMed/NCBI
47	Rebucci M, Peixoto P, Dewitte A, Wattez N, De Nuncques MA, Rezvoy N, Vautravers-Dewas C, Buisine MP, Guerin E, Peyrat JP, et al: Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance. Int J Oncol. 38:189–200. 2011.PubMed/NCBI
48	Song L, Tang JW, Owusu L, Sun MZ, Wu J and Zhang J: Galectin-3 in cancer. Clin Chim Acta. 431:185–191. 2014. View Article : Google Scholar : PubMed/NCBI
49	Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, Forbes SJ, Henderson NC, Zetterberg FR, Nilsson UJ, et al: An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 Blockade. Cancer Res. 79:1480–1492. 2019. View Article : Google Scholar : PubMed/NCBI
50	Nakahara S, Oka N and Raz A: On the role of galectin-3 in cancer apoptosis. Apoptosis. 10:267–275. 2005. View Article : Google Scholar : PubMed/NCBI
51	Yang RY, Hill PN, Hsu DK and Liu FT: Role of the carboxyl-terminal lectin domain in self-association of galectin-3. Biochemistry. 37:4086–4092. 1998. View Article : Google Scholar : PubMed/NCBI
52	Kim SJ and Chun KH: Non-classical role of Galectin-3 in cancer progression: Translocation to nucleus by carbohydrate-recognition independent manner. BMB Rep. 53:173–180. 2020. View Article : Google Scholar : PubMed/NCBI