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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Knockdown of PRKD2 Enhances Chemotherapy Sensitivity in Cervical Cancer via the TP53/CDKN1A Pathway

Author(s): Ruijing Feng, Xin Wang, Hongwei Chen, Chen Cao, Ting Liu, Tong Zhao, Huang Chen, Rui Tian, Yangyang Ni, Xun Tian, Zheng Hu*, Ji Ma* and Danni Gong*

Volume 23, Issue 2, 2023

Published on: 06 October, 2022

Page: [159 - 170] Pages: 12

DOI: 10.2174/1568009622666220822191039

Price: $65

Abstract

Background: Chemotherapy is the common treatment for cervical cancer, and the occurrence of drug resistance seriously affects the therapeutic effect of cervical cancer. Our previous study found that PRKD2 mutations occurred only in cervical cancer patients with chemotherapy resistance. However, the relationship between PRKD2 and drug resistance of cervical cancer remains unknown.

Objective: We aim to clarify the relationship between PRKD2 and drug resistance of cervical cancer.

Methods: Samples of patient tumor tissue were collected before chemotherapy and sequenced by WES. Chemotherapy clinical response was determined by measuring tumor volume. The expression of PRKD2, cell viability, and apoptosis were assessed by qRT-PCR, Western blot, CCK8, and flow cytometry in SiHa and ME180 cells after transfected with siPRKD2. The chemotherapy sensitivity signaling- related proteins were analyzed by Western blot. The expression levels of PRKD2, TP53, and CDKN1A in tissues were detected by immunohistochemistry staining.

Results: The expression of PRKD2 was higher in chemotherapy-resistant cervical cancer patients. PRKD2 knockdown increased the chemotherapy sensitivity of cervical cancer cells via the TP53/CDKN1A pathway, which led to G1 arrest and cell apoptosis. Furthermore, downregulation of PRKD2 enhances chemotherapeutic sensitivity in cervical cancer patients through the TP53/CDKN1A pathway.

Conclusion: In summary, PRKD2 may be a promising therapeutic target to improve the efficacy of chemotherapy.

Keywords: Cervical cancer, chemotherapy sensitivity, PRKD2, TP53/CDKN1A pathway, whole exome sequencing, drug resistance.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Biswas, A. Human papillomavirus (HPV) and cervical cancer. J. Indian Med. Assoc., 2000, 98(2), 53-55.
[PMID: 11016151]
[3]
Stumbar, S.E.; Stevens, M.; Feld, Z. Cervical cancer and its precursors. Prim. Care, 2019, 46(1), 117-134.
[http://dx.doi.org/10.1016/j.pop.2018.10.011] [PMID: 30704652]
[4]
Zhu, X.; Zhu, H.; Luo, H.; Zhang, W.; Shen, Z.; Hu, X. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des. Devel. Ther., 2016, 10, 1885-1895.
[http://dx.doi.org/10.2147/DDDT.S106412] [PMID: 27354763]
[5]
de Azevedo, C.R.; Thuler, L.C.; de Mello, M.J.; Ferreira, C.G. Neoadjuvant chemotherapy followed by chemoradiation in cervical carcinoma: A review. Int. J. Gynecol. Cancer, 2016, 26(4), 729-736.
[http://dx.doi.org/10.1097/IGC.0000000000000663] [PMID: 26905327]
[6]
Small, W., Jr; Bacon, M.A.; Bajaj, A.; Chuang, L.T.; Fisher, B.J.; Harkenrider, M.M.; Jhingran, A.; Kitchener, H.C.; Mileshkin, L.R.; Viswanathan, A.N.; Gaffney, D.K. Cervical cancer: A global health crisis. Cancer, 2017, 123(13), 2404-2412.
[http://dx.doi.org/10.1002/cncr.30667] [PMID: 28464289]
[7]
Assaraf, Y.G.; Brozovic, A.; Gonçalves, A.C. Linē A.; Machuqueiro, M.; Saponara, S.; Sarmento-Ribeiro, A.B.; Xavier, C.P.R.; Vasconcelos, M.H. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updat., 2019, 46, 100645.
[http://dx.doi.org/10.1016/j.drup.2019.100645] [PMID: 31585396]
[8]
Tian, X.; Wang, X.; Cui, Z.; Liu, J.; Huang, X.; Shi, C.; Zhang, M.; Liu, T.; Du, X.; Li, R.; Huang, L.; Gong, D.; Tian, R.; Cao, C.; Jin, P.; Zeng, Z.; Pan, G.; Xia, M.; Zhang, H.; Luo, B.; Xie, Y.; Li, X.; Li, T.; Wu, J.; Zhang, Q.; Chen, G.; Hu, Z.A. Fifteen-Gene classifier to predict neoadjuvant chemotherapy responses in patients with stage IB to IIB squamous cervical cancer. Adv. Sci. (Weinh.), 2021, 8(10), 2001978.
[http://dx.doi.org/10.1002/advs.202001978] [PMID: 34026427]
[9]
World Health Organization (WHO). WHO handbook for reporting results of cancer treatment. 1979, Available from: https://apps.who.int/iris/handle/10665/37200
[10]
Gately, D.P.; Howell, S.B. Cellular accumulation of the anticancer agent cisplatin: A review. Br. J. Cancer, 1993, 67(6), 1171-1176.
[http://dx.doi.org/10.1038/bjc.1993.221] [PMID: 8512802]
[11]
Shi, X.; Sun, X. Regulation of paclitaxel activity by microtubule-associated proteins in cancer chemotherapy. Cancer Chemother. Pharmacol., 2017, 80(5), 909-917.
[http://dx.doi.org/10.1007/s00280-017-3398-2] [PMID: 28741098]
[12]
Kaiser, A.M.; Attardi, L.D. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ., 2018, 25(1), 93-103.
[http://dx.doi.org/10.1038/cdd.2017.171] [PMID: 29099489]
[13]
Blagih, J.; Buck, M.D.; Vousden, K.H. p53, cancer and the immune response. J. Cell Sci., 2020, 133(5), jcs237453.
[http://dx.doi.org/10.1242/jcs.237453] [PMID: 32144194]
[14]
Chen, C.; Zhao, Z.; Tang, S.; Zhang, C. Rab like protein 1 A is upregulated by cisplatin treatment and partially inhibits chemoresistance by regulating p53 activity. Oncol. Lett., 2018, 16(4), 4593-4599.
[http://dx.doi.org/10.3892/ol.2018.9205] [PMID: 30197676]
[15]
Pothuraju, R.; Rachagani, S.; Krishn, S.R.; Chaudhary, S.; Nimmakayala, R.K.; Siddiqui, J.A.; Ganguly, K.; Lakshmanan, I.; Cox, J.L.; Mallya, K.; Kaur, S.; Batra, S.K. Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Mol. Cancer, 2020, 19(1), 37.
[http://dx.doi.org/10.1186/s12943-020-01156-y] [PMID: 32098629]
[16]
Yang, L.; Zhou, Y.; Li, Y.; Zhou, J.; Wu, Y.; Cui, Y.; Yang, G.; Hong, Y. Mutations of p53 and KRAS activate NF-κB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. Cancer Lett., 2015, 357(2), 520-526.
[http://dx.doi.org/10.1016/j.canlet.2014.12.003] [PMID: 25499080]
[17]
Zhao, X.; Sun, W.; Ren, Y.; Lu, Z. Therapeutic potential of p53 reactivation in cervical cancer. Crit. Rev. Oncol. Hematol., 2021, 157, 103182.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103182] [PMID: 33276182]
[18]
El-Deiry, W.S. p21(WAF1) mediates cell-cycle inhibition, relevant to cancer suppression and therapy. Cancer Res., 2016, 76(18), 5189-5191.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2055] [PMID: 27635040]
[19]
El-Deiry, W.; Tokino, T.; Velculescu, V.E.; Levy, D.B.; Parsons, R.; Trent, J.M.; Lin, D.; Mercer, W.E.; Kinzler, K.W.; Vogelstein, B. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75(4), 817-825.
[http://dx.doi.org/10.1016/0092-8674(93)90500-P] [PMID: 8242752]
[20]
Cheng, Y.; Hu, Y.; Wang, H.; Zhao, Z.; Jiang, X.; Zhang, Y.; Zhang, J.; Tong, Y.; Qiu, X. Ring finger protein 19A is overexpressed in non-small cell lung cancer and mediates p53 ubiquitin-degradation to promote cancer growth. J. Cell. Mol. Med., 2021, 25(16), 7796-7808.
[http://dx.doi.org/10.1111/jcmm.16674] [PMID: 34184814]
[21]
Deng, L.; Yao, P.; Li, L.; Ji, F.; Zhao, S.; Xu, C.; Lan, X.; Jiang, P. p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival. Nat. Commun., 2020, 11(1), 1755.
[http://dx.doi.org/10.1038/s41467-020-15573-6] [PMID: 32273511]
[22]
Wang, J.; Yang, F.; Zhuang, J.; Huo, Q.; Li, J.; Xie, N. TRIM58 inactivates p53/p21 to promote chemoresistance via ubiquitination of DDX3 in breast cancer. Int. J. Biochem. Cell Biol., 2022, 143, 106140.
[http://dx.doi.org/10.1016/j.biocel.2021.106140] [PMID: 34954155]
[23]
Hartlerode, A.; Odate, S.; Shim, I.; Brown, J.; Scully, R. Cell cycle-dependent induction of homologous recombination by a tightly regulated I-SceI fusion protein. PLoS One, 2011, 6(3), e16501.
[http://dx.doi.org/10.1371/journal.pone.0016501] [PMID: 21408059]
[24]
Rothkamm, K.; Krüger, I.; Thompson, L.H.; Löbrich, M. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol. Cell. Biol., 2003, 23(16), 5706-5715.
[http://dx.doi.org/10.1128/MCB.23.16.5706-5715.2003] [PMID: 12897142]
[25]
Panier, S.; Durocher, D. Push back to respond better: regulatory inhibition of the DNA double-strand break response. Nat. Rev. Mol. Cell Biol., 2013, 14(10), 661-672.
[http://dx.doi.org/10.1038/nrm3659] [PMID: 24002223]
[26]
Saintigny, Y.; Delacôte, F.; Varès, G.; Petitot, F.; Lambert, S.; Averbeck, D.; Lopez, B.S. Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J., 2001, 20(14), 3861-3870.
[http://dx.doi.org/10.1093/emboj/20.14.3861] [PMID: 11447127]
[27]
Liu, Q.; Li, W.; Zhou, Y.; Jian, J.; Han, S.; Liu, C.; Li, W.; Zhu, X.; Ma, D.; Ji, M.; Ji, C. PRKD2 promotes progression and chemoresistance of AML via regulating notch1 pathway. OncoTargets Ther., 2019, 12, 10931-10941.
[http://dx.doi.org/10.2147/OTT.S233234] [PMID: 31849496]
[28]
el-Deiry, W.S.; Harper, J.W.; O’Connor, P.M.; Velculescu, V.E.; Canman, C.E.; Jackman, J.; Pietenpol, J.A.; Burrell, M.; Hill, D.E.; Wang, Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res., 1994, 54(5), 1169-1174.
[PMID: 8118801]

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