Glucose-regulated Protein 78 Mediates the Anticancer Efficacy of Shikonin in Hormone-refractory Prostate Cancer Cells

Overview

Journal Tumour Biol

Publisher Sage Publications

Specialty Oncology

Date 2015 Feb 12

PMID 25669168

Citations 6

Authors

Li-Jen Kuo

Chien-Yu Huang

Wan-Li Cheng

Chin-Sheng Hung

Chun-Te Wu

Feng-Yen Lin

Yu-Jia Chang

Ming-Te Huang

Affiliations

Soon will be listed here.

Abstract

Glucose-regulated protein 78 (GRP78) is a key modulator of prostate cancer progression and therapeutic resistance. Prostate cancer is a worldwide health problem, and therapeutic resistance is a critical obstacle for the treatment of hormone-refractory prostate cancer patients. Shikonin inhibits prostate cancer proliferation and metastasis. However, the role of GRP78 in the cytotoxic effect of shikonin in prostate cancer cells remains unclear. GRP78 expression was abolished using small interfering RNA (siRNA), and the anticancer effects of shikonin were assessed using MTT assays, the XCELLigence biosensor, flow cytometric cell cycle analysis, and Annexin V-PI apoptotic assays. PC-3 cells expressed more GRP78 than DU-145 cells, and the MTT assays revealed that DU-145 cells were more sensitive to shikonin than PC-3 cells. GRP78 knockdown (GRP78KD) PC-3 cells were more sensitive to shikonin treatment than scrambled siRNA control cells. Based on cell cycle analysis and AnnexinV-PI apoptotic assays, apoptosis dramatically increased in GRP78KD cells compared with the control PC-3 in response to shikonin. Finally, in response to shikonin treatment, Mcl-1 and Bcl-2 levels increased in the scrambled control cells treated with shikonin, whereas Bcl-2 decreased and Mcl-1 slightly increased in the GRP78KD PC-3 cells. The levels of Bax and Bad did not change in the scrambled control or GRP78KD cells after shikonin treatment. These results are consistent with the increased sensitivity to shikonin after knockdown of GRP78. GRP78 expression may determine the therapeutic efficacy of shikonin against prostate cancer cells.

Citing Articles

Role of the GRP78-c-Src signaling pathway on osteoblast differentiation of periodontal ligament fibroblasts induced by cyclic mechanical stretch.

Hu J, Cui Z, Huang K, Su R, Zhao S Hua Xi Kou Qiang Yi Xue Za Zhi. 2024; 42(3):304-312.

PMID: 39049649 PMC: 11190863. DOI: 10.7518/hxkq.2024.2023354.

Transketolase promotes colorectal cancer metastasis through regulating AKT phosphorylation.

Li M, Zhao X, Yong H, Xu J, Qu P, Qiao S Cell Death Dis. 2022; 13(2):99.

PMID: 35110545 PMC: 8810869. DOI: 10.1038/s41419-022-04575-5.

Shikonin enhances the antitumor effect of cabazitaxel in prostate cancer stem cells and reverses cabazitaxel resistance by inhibiting ABCG2 and ALDH3A1.

Wang L, Stadlbauer B, Lyu C, Buchner A, Pohla H Am J Cancer Res. 2020; 10(11):3784-3800.

PMID: 33294267 PMC: 7716147.

The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer.

Hoter A, Rizk S, Naim H Cancers (Basel). 2019; 11(8).

PMID: 31426412 PMC: 6721600. DOI: 10.3390/cancers11081194.

Luo C, Fan W, Jiang Y, Zhou S, Cheng W Med Sci Monit. 2018; 24:2197-2209.

PMID: 29650944 PMC: 5916091. DOI: 10.12659/msm.906413.

References

Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R . Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004; 10(1):33-9. DOI: 10.1038/nm972. View

Karantanos T, Corn P, Thompson T . Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013; 32(49):5501-11. PMC: 3908870. DOI: 10.1038/onc.2013.206. View

Kim S, Cho H, Kang J, Kang H, Yoo T . Inhibition of androgen receptor expression with small interfering RNA enhances cancer cell apoptosis by suppressing survival factors in androgen insensitive, late stage LNCaP cells. ScientificWorldJournal. 2013; 2013:519397. PMC: 3580912. DOI: 10.1155/2013/519397. View

Fan Y, Jin S, He J, Shao Z, Yan J, Feng T . Effect of β,β-dimethylacrylshikonin on inhibition of human colorectal cancer cell growth in vitro and in vivo. Int J Mol Sci. 2012; 13(7):9184-9193. PMC: 3430290. DOI: 10.3390/ijms13079184. View

Ghosh N, Ghosh R, Bhat Z, Mandal V, Bachar S, Nima N . Advances in herbal medicine for treatment of ischemic brain injury. Nat Prod Commun. 2014; 9(7):1045-55. View

Sowinski S, Jolly C, Berninghausen O, Purbhoo M, Chauveau A, Kohler K . Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol. 2008; 10(2):211-9. DOI: 10.1038/ncb1682. View

Sternberg C, Petrylak D, Madan R, Parker C . Progress in the treatment of advanced prostate cancer. Am Soc Clin Oncol Educ Book. 2014; :117-31. DOI: 10.14694/EdBook_AM.2014.34.117. View

Chen Y, Zheng L, Liu J, Zhou Z, Cao X, Lv X . Shikonin inhibits prostate cancer cells metastasis by reducing matrix metalloproteinase-2/-9 expression via AKT/mTOR and ROS/ERK1/2 pathways. Int Immunopharmacol. 2014; 21(2):447-55. DOI: 10.1016/j.intimp.2014.05.026. View

Yang H, Zhou P, Huang H, Chen D, Ma N, Cui Q . Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer. 2009; 124(10):2450-9. PMC: 2707765. DOI: 10.1002/ijc.24195. View

10.

Harris W, Mostaghel E, Nelson P, Montgomery B . Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol. 2009; 6(2):76-85. PMC: 2981403. DOI: 10.1038/ncpuro1296. View

11.

Tai C, Wang J, Su H, Tai C, Wang C, Wu C . Glucose-regulated protein 94 modulates the therapeutic efficacy to taxane in cervical cancer cells. Tumour Biol. 2013; 35(1):403-10. DOI: 10.1007/s13277-013-1056-9. View

12.

Lee M, Kao S, Hunag J, Sheu G, Yeh C, Hseu Y . Shikonin time-dependently induced necrosis or apoptosis in gastric cancer cells via generation of reactive oxygen species. Chem Biol Interact. 2014; 211:44-53. DOI: 10.1016/j.cbi.2014.01.008. View

13.

Guo J, Chen X, Liu J, Lin H, Han H, Liu H . Novel shikonin derivatives targeting tubulin as anticancer agents. Chem Biol Drug Des. 2014; 84(5):603-15. DOI: 10.1111/cbdd.12353. View

14.

Heinlein C, Chang C . Androgen receptor in prostate cancer. Endocr Rev. 2004; 25(2):276-308. DOI: 10.1210/er.2002-0032. View

15.

Wang Y, Zhou Y, Jia G, Han B, Liu J, Teng Y . Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway. Biochem Pharmacol. 2014; 88(3):322-33. DOI: 10.1016/j.bcp.2014.01.041. View

16.

Chang Y, Chiu C, Wu C, An J, Wu C, Liu T . Glucose-regulated protein 78 (GRP78) silencing enhances cell migration but does not influence cell proliferation in hepatocellular carcinoma. Ann Surg Oncol. 2010; 17(6):1703-9. DOI: 10.1245/s10434-010-0912-8. View

17.

Wu C, Wang W, Chen M, Su H, Chen W, Wu C . Glucose-regulated protein 78 mediates hormone-independent prostate cancer progression and metastasis through maspin and COX-2 expression. Tumour Biol. 2013; 35(1):195-204. DOI: 10.1007/s13277-013-1024-4. View

18.

Yoshihisa Y, Hassan M, Furusawa Y, Tabuchi Y, Kondo T, Shimizu T . Alkannin, HSP70 inducer, protects against UVB-induced apoptosis in human keratinocytes. PLoS One. 2012; 7(10):e47903. PMC: 3478268. DOI: 10.1371/journal.pone.0047903. View

19.

Isaacs J, Isaacs W . Androgen receptor outwits prostate cancer drugs. Nat Med. 2004; 10(1):26-7. DOI: 10.1038/nm0104-26. View

20.

de Ridder G, Ray R, Misra U, Pizzo S . Modulation of the unfolded protein response by GRP78 in prostate cancer. Methods Enzymol. 2011; 489:245-57. DOI: 10.1016/B978-0-12-385116-1.00014-5. View