Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis

Authors: Xinfang Yu, Wei Li, Zhenkun Xia, Li Xie, Xiaolong Ma, Qi Liang, Lijun Liu, Jian Wang, Xinmin Zhou, Yifeng Yang, Haidan Liu

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed.

Methods

We used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin.

Results

The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage.

Conclusions

The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.
Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed
2.
Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2009;66(8):1326–36.CrossRefPubMed
3.
Lee WS, Park YL, Kim N, Oh HH, Son DJ, Kim MY, et al. Myeloid cell leukemia-1 regulates the cell growth and predicts prognosis in gastric cancer. Int J Oncol. 2015;46(5):2154–62.PubMed
4.
Craig RW. MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis. Leukemia. 2002;16(4):444–54.CrossRefPubMed
5.
Sieghart W, Losert D, Strommer S, Cejka D, Schmid K, Rasoul-Rockenschaub S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol. 2006;44(1):151–7.CrossRefPubMed
6.
Miyamoto Y, Hosotani R, Wada M, Lee JU, Koshiba T, Fujimoto K, et al. Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology. 1999;56(1):73–82.CrossRefPubMed
7.
Dash R, Richards JE, Su ZZ, Bhutia SK, Azab B, Rahmani M, et al. Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine. Cancer Res. 2010;70(12):5034–45.CrossRefPubMedPubMedCentral
8.
Whitsett TG, Mathews IT, Cardone MH, Lena RJ, Pierceall WE, Bittner M, et al. Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. Mol Cancer Res. 2014;12(4):550–9.CrossRefPubMedPubMedCentral
9.
Liu H, Yang J, Yuan Y, Xia Z, Chen M, Xie L, et al. Regulation of Mcl-1 by constitutive activation of NF-kappaB contributes to cell viability in human esophageal squamous cell carcinoma cells. BMC Cancer. 2014;14:98.CrossRefPubMedPubMedCentral
10.
Leu CM, Chang C, Hu C. Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene. 2000;19(13):1665–75.CrossRefPubMed
11.
Feng YB, Lin DC, Shi ZZ, Wang XC, Shen XM, Zhang Y, et al. Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma. Int J Cancer. 2009;124(3):578–88.CrossRefPubMed
12.
Ding Q, He X, Hsu JM, Xia W, Chen CT, Li LY, et al. Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization. Mol Cell Biol. 2007;27(11):4006–17.CrossRefPubMed
13.
Yin W, Nie Y, Zhang Z, Xie L. He X: miR-193b acts as a cisplatin sensitizer via the caspase-3-dependent pathway in HCC chemotherapy. Oncol Rep. 2015;34(1):368–74.PubMed
14.
Hu J, Xu C, Cheng B, Jin L, Li J, Gong Y, et al. Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy. Tumour Biol. 2016;37(1):331–9.CrossRefPubMed
15.
Tanaka N, Patel AA, Wang J, Frederick MJ, Kalu NN, Zhao M, et al. Wee-1 Kinase inhibition sensitizes high-risk HPV+ HNSCC to apoptosis accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic proteins. Clin Cancer Res. 2015;21(21):4831–44.CrossRefPubMedPubMedCentral
16.
Akagi H, Higuchi H, Sumimoto H, Igarashi T, Kabashima A, Mizuguchi H, et al. Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. Gastric Cancer. 2013;16(1):100–10.CrossRefPubMed
17.
Stoner GD, Kaighn ME, Reddel RR, Resau JH, Bowman D, Naito Z, et al. Establishment and characterization of SV40 T-antigen immortalized human esophageal epithelial cells. Cancer Res. 1991;51(1):365–71.PubMed
18.
Liu H, Hwang J, Li W, Choi TW, Liu K, Huang Z, et al. A derivative of chrysin suppresses two-stage skin carcinogenesis by inhibiting mitogen- and stress-activated kinase 1. Cancer Prev Res (Phila). 2014;7(1):74–85.CrossRef
19.
Liu H, Liu K, Huang Z, Park CM, Thimmegowda NR, Jang JH, et al. A chrysin derivative suppresses skin cancer growth by inhibiting cyclin-dependent kinases. J Biol Chem. 2013;288(36):25924–37.CrossRefPubMedPubMedCentral
20.
Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005;19(11):1294–305.CrossRefPubMedPubMedCentral
21.
van Delft MF, Huang DC. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res. 2006;16(2):203–13.CrossRefPubMed
22.
23.
Song L, Coppola D, Livingston S, Cress D, Haura EB. Mcl-1 regulates survival and sensitivity to diverse apoptotic stimuli in human non-small cell lung cancer cells. Cancer Biol Ther. 2005;4(3):267–76.CrossRefPubMed
24.
Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS, et al. A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther. 2014;13(3):565–75.CrossRefPubMed
25.
Kitada S, Zapata JM, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood. 2000;96(2):393–7.PubMed
26.
Hahntow IN, Schneller F, Oelsner M, Weick K, Ringshausen I, Fend F, et al. Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia. 2004;18(4):747–55.CrossRefPubMed
27.
Chen R, Wierda WG, Chubb S, Hawtin RE, Fox JA, Keating MJ, et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009;113(19):4637–45.CrossRefPubMedPubMedCentral
28.
Faber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, et al. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov. 2013;4(1):42–52.CrossRefPubMedPubMedCentral
29.
Sun H, Kapuria V, Peterson LF, Fang D, Bornmann WG, Bartholomeusz G, et al. Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood. 2011;117(11):3151–62.CrossRefPubMed
30.
Wei J, Kitada S, Rega MF, Emdadi A, Yuan H, Cellitti J, et al. Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther. 2009;8(4):904–13.CrossRefPubMedPubMedCentral
31.
Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A. 2007;104(49):19512–7.CrossRefPubMedPubMedCentral
32.
Wei J, Stebbins JL, Kitada S, Dash R, Placzek W, Rega MF, et al. BI-97C1, an optically pure Apogossypol derivative as pan-active inhibitor of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 2010;53(10):4166–76.CrossRefPubMedPubMedCentral
33.
Dash R, Azab B, Quinn BA, Shen X, Wang XY, Das SK, et al. Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. Proc Natl Acad Sci U S A. 2011;108(21):8785–90.CrossRefPubMedPubMedCentral
34.
Kazi A, Sun J, Doi K, Sung SS, Takahashi Y, Yin H, et al. The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. J Biol Chem. 2011;286(11):9382–92.CrossRefPubMed
35.
Quinn BA, Dash R, Azab B, Sarkar S, Das SK, Kumar S, et al. Targeting Mcl-1 for the therapy of cancer. Expert Opin Investig Drugs. 2011;20(10):1397–411.CrossRefPubMedPubMedCentral
36.
Leverson JD, Zhang H, Chen J, Tahir SK, Phillips DC, Xue J, et al. Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax). Cell Death Dis. 2015;6:e1590.CrossRefPubMedPubMedCentral
37.
38.
Li J, Viallet J, Haura EB. A small molecule pan-Bcl-2 family inhibitor, GX15-070, induces apoptosis and enhances cisplatin-induced apoptosis in non-small cell lung cancer cells. Cancer Chemother Pharmacol. 2008;61(3):525–34.CrossRefPubMed
39.
Ren T, Shan J, Li M, Qing Y, Qian C, Wang G, et al. Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer. Drug Des Devel Ther. 2015;9:2887–910.PubMedPubMedCentral
40.
Maji S, Samal SK, Pattanaik L, Panda S, Quinn BA, Das SK, et al. Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. Oncotarget. 2015;6(18):16623–37.CrossRefPubMedPubMedCentral
41.
Quinn BA, Dash R, Sarkar S, Azab B, Bhoopathi P, Das SK, et al. Pancreatic cancer combination therapy using a BH3 mimetic and a synthetic tetracycline. Cancer Res. 2015;75(11):2305–15.CrossRefPubMedPubMedCentral
42.
Varadarajan S, Vogler M, Butterworth M, Dinsdale D, Walensky LD, Cohen GM. Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ. 2013;20(11):1475–84.CrossRefPubMedPubMedCentral
43.
Chen S, Dai Y, Harada H, Dent P, Grant S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 2007;67(2):782–91.CrossRefPubMed
44.
Faber AC, Farago AF, Costa C, Dastur A, Gomez-Caraballo M, Robbins R, et al. Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. Proc Natl Acad Sci U S A. 2015;112(11):E1288–96.CrossRefPubMedPubMedCentral
45.
46.
Gelinas C, White E. BH3-only proteins in control: specificity regulates MCL-1 and BAK-mediated apoptosis. Genes Dev. 2005;19(11):1263–8.CrossRefPubMed
47.
Aichberger KJ, Mayerhofer M, Krauth MT, Skvara H, Florian S, Sonneck K, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood. 2005;105(8):3303–11.CrossRefPubMed
48.
Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood. 2002;99(6):1885–93.CrossRefPubMed
49.
Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F, et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 2003;17(12):1475–86.CrossRefPubMedPubMedCentral
50.
Mandelin AM 2nd, Pope RM. Myeloid cell leukemia-1 as a therapeutic target. Expert Opin Ther Targets. 2007;11(3):363–73.CrossRefPubMed
51.
Liu H, Eksarko P, Temkin V, Haines GK 3rd, Perlman H, Koch AE, et al. Mcl-1 is essential for the survival of synovial fibroblasts in rheumatoid arthritis. J Immunol. 2005;175(12):8337–45.CrossRefPubMed
Metadata
Title
Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis
Authors
Xinfang Yu
Wei Li
Zhenkun Xia
Li Xie
Xiaolong Ma
Qi Liang
Lijun Liu
Jian Wang
Xinmin Zhou
Yifeng Yang
Haidan Liu
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3442-y

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

High neutrophil-to-lymphocyte ratios confer poor prognoses in patients with small cell lung cancer

Research article

Cytotoxicity of replication-competent adenoviruses powered by an exogenous regulatory region is not linearly correlated with the viral infectivity/gene expression or with the E1A-activating ability but is associated with the p53 genotypes

Research article

CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer

Research article

MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting Prohibitin 1

Research article

The safety and efficacy of percutaneous intraductal radiofrequency ablation in unresectable malignant biliary obstruction: A single-institution experience

Study protocol

Internet-based perioperative exercise program in patients with Barrett’s carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits