Suppression of GRP78 sensitizes human colorectal cancer cells to oxaliplatin by downregulation of CD24

Xi,Jingle; Chen,Yufan; Huang,Shangbin; Cui,Fei; Wang,Xinying

doi:10.3892/ol.2018.8549

Suppression of GRP78 sensitizes human colorectal cancer cells to oxaliplatin by downregulation of CD24

Authors:
- Jingle Xi
- Yufan Chen
- Shangbin Huang
- Fei Cui
- Xinying Wang
View Affiliations

Affiliations: Department of Oncology, Nanfang Hospital, Guangzhou, Guangdong 510515, P.R. China, Department of Orthopaedic Surgery, Nanfang Hospital, Guangzhou, Guangdong 510515, P.R. China, Department of General Surgery, Taixin Hospital, Dongguan, Guangdong 523000, P.R. China, Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
Published online on: April 20, 2018 https://doi.org/10.3892/ol.2018.8549
Pages: 9861-9867
Copyright : © Xi et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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

Glucose‑regulated protein 78 (GRP78) is an endoplasmic reticulum stress signaling regulator with anti‑apoptotic properties. It has been demonstrated to promote tumor proliferation, survival and metastasis, and to confer resistance against a large variety of therapies. CD24 is a glycosyl‑phosphatidylinositol‑anchored protein, which is known to have a role in tumor progression, particularly in colorectal cancer (CRC). In the present study, oxaliplatin (L‑OHP) was demonstrated to decrease the expression of CD24 in HT29 cells. Knockdown of CD24 using small interfering RNA resulted in sensitization of HT29 cells to L‑OHP. By contrast, overexpression of CD24 rendered SW480 cells resistant to L‑OHP, which indicated that CD24 antagonized L‑OHP‑induced cytotoxicity. A co‑immunoprecipitation assay revealed that GRP78 physically associates with CD24. L‑OHP suppresses the expression of GRP78 and CD24, in part come from the inhibition of interaction between the two. Suppression of GRP78 caused downregulation of CD24 expression and enhanced L‑OHP‑induced CD24 inhibition. Furthermore, down‑regulation of GPR78 with a pharmacological inhibitor sensitized the CRC cells to L‑OHP. Collectively, the present results indicate that CD24 antagonizes L‑OHP‑induced cytotoxicity and that GRP78 is involved in this process. A novel mechanism via which CRC cells acquire resistance to L‑OHP was thereby revealed. Use of a combination of compounds which suppress GRP78 may help to improve the effectiveness of L‑OHP in the treatment of CRC.

View Figures

View References

1	Bretz N, Noske A, Keller S, Erbe-Hofmann N, Schlange T, Salnikov AV, Moldenhauer G, Kristiansen G and Altevogt P: CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion. Clin Exp Metastasis. 29:27–38. 2012. View Article : Google Scholar : PubMed/NCBI
2	Keeratichamroen S, Leelawat K, Thongtawee T, Narong S, Aegem U, Tujinda S, Praditphol N and Tohtong R: Expression of CD24 in cholangiocarcinoma cells is associated with disease progression and reduced patient survival. Int J Oncol. 39:873–881. 2011.PubMed/NCBI
3	Agrawal S, Kuvshinoff BW, Khoury T, Yu J, Javle MM, LeVea C, Groth J, Coignet LJ and Gibbs JF: CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg. 11:445–451. 2007. View Article : Google Scholar : PubMed/NCBI
4	Kwon MJ, Han J, Seo JH, Song K, Jeong HM, Choi JS, Kim YJ, Lee SH, Choi YL and Shin YK: CD24 overexpression is associated with poor prognosis in luminal A and triple-negative breast cancer. PLoS One. 10:e1391122015. View Article : Google Scholar
5	Tang MR, Wang YX, Guo S, Han SY, Li HH and Jin SF: CD24 expression predicts poor prognosis for patients with cutaneous malignant melanoma. Int J Clin Exp Med. 7:4337–4341. 2014.PubMed/NCBI
6	Wu JX, Zhao YY, Wu X and An HX: Clinicopathological and prognostic significance of CD24 overexpression in patients with gastric cancer: A meta-analysis. PLoS One. 9:e1147462014. View Article : Google Scholar : PubMed/NCBI
7	Tanaka T, Terai Y, Kogata Y, Ashihara K, Maeda K, Fujiwara S, Yoo S, Tanaka Y, Tsunetoh S, Sasaki H, et al: CD24 expression as a marker for predicting clinical outcome and invasive activity in uterine cervical cancer. Oncol Rep. 34:2282–2288. 2015. View Article : Google Scholar : PubMed/NCBI
8	Overdevest JB, Thomas S, Kristiansen G, Hansel DE, Smith SC and Theodorescu D: CD24 offers a therapeutic target for control of bladder cancer metastasis based on a requirement for lung colonization. Cancer Res. 71:3802–3811. 2011. View Article : Google Scholar : PubMed/NCBI
9	Sagiv E, Starr A, Rozovski U, Khosravi R, Altevogt P, Wang T and Arber N: Targeting CD24 for treatment of colorectal and pancreatic cancer by monoclonal antibodies or small interfering RNA. Cancer Res. 68:2803–2812. 2008. View Article : Google Scholar : PubMed/NCBI
10	Smith SC, Oxford G, Wu Z, Nitz MD, Conaway M, Frierson HF, Hampton G and Theodorescu D: The metastasis-associated gene CD24 is regulated by Ral GTPase and is a mediator of cell proliferation and survival in human cancer. Cancer Res. 66:1917–1922. 2006. View Article : Google Scholar : PubMed/NCBI
11	Su D, Deng H, Zhao X, Zhang X, Chen L, Chen X, Li Z, Bai Y, Wang Y, Zhong Q, et al: Targeting CD24 for treatment of ovarian cancer by short hairpin RNA. Cytotherapy. 11:642–652. 2009. View Article : Google Scholar : PubMed/NCBI
12	Suyama K, Onishi H, Imaizumi A, Shinkai K, Umebayashi M, Kubo M, Mizuuchi Y, Oda Y, Tanaka M, Nakamura M and Katano M: CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells. Cancer Lett. 374:44–53. 2016. View Article : Google Scholar : PubMed/NCBI
13	Ke J, Wu X, Wu X, He X, Lian L, Zou Y, He X, Wang H, Luo Y, Wang L and Lan P: A subpopulation of CD24 cells in colon cancer cell lines possess stem cell characteristics. Neoplasma. 59:282–288. 2012. View Article : Google Scholar : PubMed/NCBI
14	Salnikov AV, Bretz NP, Perne C, Hazin J, Keller S, Fogel M, Herr I, Schlange T, Moldenhauer G and Altevogt P: Antibody targeting of CD24 efficiently retards growth and influences cytokine milieu in experimental carcinomas. Br J Cancer. 108:1449–1459. 2013. View Article : Google Scholar : PubMed/NCBI
15	Parker AL, Turner N, McCarroll JA and Kavallaris M: βIII-tubulin alters glucose metabolism and stress response signaling to promote cell survival and proliferation in glucose-starved non-small cell lung cancer cells. Carcinogenesis. 37:787–798. 2016. View Article : Google Scholar : PubMed/NCBI
16	Zoni E, Chen L, Karkampouna S, Granchi Z, Verhoef EI, La Manna F, Kelber J, Pelger RCM, Henry MD, Snaar-Jagalska E, et al: CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer. Oncogene. 17:4739–4749. 2017. View Article : Google Scholar
17	Ogawa H, Kaira K, Takahashi K, Shimizu A, Altan B, Yoshinari D, Asao T and Oyama T: Prognostic role of BiP/GRP78 expression as ER stress in patients with gastric adenocarcinoma. Cancer Biomark. 7:273–281. 2017. View Article : Google Scholar
18	Kawiak A, Domachowska A, Jaworska A and Lojkowska E: Plumbagin sensitizes breast cancer cells to tamoxifen-induced cell death through GRP78 inhibition and Bik upregulation. Sci Rep. 13:437812017. View Article : Google Scholar
19	Lizardo MM, Morrow JJ, Miller TE, Hong ES, Ren L, Mendoza A, Halsey CH, Scacheri PC, Helman LJ and Khanna C: Upregulation of glucose-regulated protein 78 in metastatic cancer cells is necessary for lung metastasis progression. Neoplasia. 28:699–710. 2016. View Article : Google Scholar
20	Gonzalez-Gronow M, Selim MA, Papalas J and Pizzo SV: GRP78: A multifunctional receptor on the cell surface. Antioxid Redox Signal. 11:2299–2306. 2009. View Article : Google Scholar : PubMed/NCBI
21	Wang M, Wey S, Zhang Y, Ye R and Lee AS: Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal. 11:2307–2316. 2009. View Article : Google Scholar : PubMed/NCBI
22	Rauschert N, Ndlein SB, Holzinger E, Hensel F, Müller-Hermelink HK and Vollmers HP: A new tumor-specific variant of GRP78 as target for antibody-based therapy. Lab Invest. 88:375–386. 2008. View Article : Google Scholar : PubMed/NCBI
23	Papalas JA, Vollmer RT, Gonzalezgronow M, Pizzo SV, Burchette J, Youens KE, Johnson KB and Selim MA: Patterns of GRP78 and MTJ1 expression in primary cutaneous malignant melanoma. Mod Pathol. 23:134–143. 2010. View Article : Google Scholar : PubMed/NCBI
24	Fu W, Wu X, Li J, Mo Z, Yang Z, Huang W and Ding Q: Upregulation of GRP78 in renal cell carcinoma and its significance. Urology. 75:603–607. 2010. View Article : Google Scholar : PubMed/NCBI
25	Xia YZ, Yang L, Xue GM, Zhang C, Guo C, Yang YW, Li SS, Zhang LY, Guo QL and Kong LY: Combining GRP78 suppression and MK2206-induced Akt inhibition decreases doxorubicin-induced P-glycoprotein expression and mitigates chemoresistance in human osteosarcoma. Oncotarget. 7:56371–56382. 2016. View Article : Google Scholar : PubMed/NCBI
26	Yerlikaya A, Erdogan E, Okur E, Yerlikaya S and Savran B: A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib. Oncol Lett. 12:323–330. 2016. View Article : Google Scholar : PubMed/NCBI
27	Kong DH, Zhang Q, Meng X, Zong ZH, Li C, Liu BQ, Guan Y and Wang HQ: BAG3 sensitizes cancer cells exposed to DNA damaging agents via direct interaction with GRP78. Biochim Biophys Acta. 1833:3245–3253. 2013. View Article : Google Scholar : PubMed/NCBI
28	Golden EB, Cho HY, Jahanian A, Hofman FM, Louie SG, Schönthal AH and Chen TC: Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus. 37:E122014. View Article : Google Scholar : PubMed/NCBI
29	Luvsandagva B, Nakamura K, Kitahara Y, Aoki H, Murata T, Ikeda S and Minegishi T: GRP78 induced by estrogen plays a role in the chemosensitivity of endometrial cancer. Gynecol Oncol. 126:132–139. 2012. View Article : Google Scholar : PubMed/NCBI
30	Gifford JB and Hill R: GRP78 influences chemoresistance and prognosis in cancer. Curr Drug Targets. Jun 15–2017.(Epub ahead of print).
31	Soni P, Qayoom S, Husain N, Kumar P, Chandra A, Ojha BK and Gupta RK: CD24 and nanog expression in stem cells in glioblastoma: Correlation with response to chemoradiation and overall survival. Asian Pac J Cancer Prev. 18:2215–2219. 2017.PubMed/NCBI
32	Kristiansen G, Machado E, Bretz N, Rupp C, Winzer KJ, König AK, Moldenhauer G, Marmé F, Costa J and Altevogt P: Molecular and clinical dissection of CD24 antibody specificity by a comprehensive comparative analysis. Lab Invest. 90:1102–1116. 2010. View Article : Google Scholar : PubMed/NCBI
33	Wang X, Zhang Y, Zhao Y, Liang Y, Xiang C, Zhou H, Zhang H, Zhang Q, Qing H, Jiang B, et al: CD24 promoted cancer cell angiogenesis via Hsp90-mediated STAT3/VEGF signalling pathway in colorectal cancer. Oncotarget. 7:55663–55676. 2016.PubMed/NCBI
34	Huang YN, Guo X, You LP, Wang CJ, Liu JQ and Li YL: Lysosome-associated protein transmembrane4β is involved in multidrug resistance processes of colorectal cancer. Oncol Lett. 14:5229–5234. 2017.PubMed/NCBI