Knockdown of the long noncoding RNA HOTTIP inhibits cell proliferation and enhances cell sensitivity to cisplatin by suppressing the Wnt/β‐catenin pathway in prostate cancer

Abstract

Background: Prostate cancer (PCa) is a prevalent and deadly cancer worldwide. Considering the malignant progression and therapeutic resistance of PCa, further dissection of the underlying mechanisms and exploration of novel therapeutic targets for PCa are urgently needed. The long noncoding RNA HOTTIP has recently been revealed as an oncogenic regulator in different cancers; however, whether HOTTIP is involved in PCa remains poorly understood. Here, we examined the crucial roles of HOTTIP in the proliferation and chemoresistance of PCa.Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the HOTTIP messenger RNA (mRNA) levels in PCa samples from patients and PCa cells. Then, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and cell cycle and flow cytometry assays were performed to investigate the proliferation and cisplatin-resistance of PCa cells with silenced HOTTIP compared with a negative control. We applied Western blotting, qRT-PCR and a TOP/FOP assay to explore the relevant mechanisms.Results: In this study, we found that the HOTTIP mRNA levels were increased in the PCa patient samples and PCa cell lines compared with the controls. The knockdown of HOTTIP not only inhibited the proliferation of PCa cells but also facilitated cell cycle arrest and chemosensitivity to cisplatin. Furthermore, the qRT-PCR, Western blotting, TOP/FOP assays, MTT assay, and flow cytometry revealed that Wnt/β-catenin signaling was related to the regulation of HOTTIP in cell proliferation, cell cycle arrest, and chemoresistance to cisplatin in PCa. Conclusion: Taken together, our findings suggest that HOTTIP may be a potent therapeutic target for PCa, and HOTTIP inhibitors might be regarded as effective strategies for PCa therapy. K E Y W O R D S chemoresistance, HOTTIP, long noncoding RNA (lncRNA), proliferation, prostate cancer (PCa), Wnt/β-catenin J Cell Biochem. 2019;120:8965-8974. wileyonlinelibrary.com/journal/jcb of the long noncoding RNA HOTTIP inhibits cell proliferation and enhances cell sensitivity to cisplatin by suppressing the Wnt/β-catenin pathway in prostate cancer. J Cell Biochem. 2019;120:8965-8974.

Regulation of ABCG2 expression by Wnt5a through FZD7 in human pancreatic cancer cells

“…Cancer cells with a stem cell phenotype are more resistant to anti-cancer drugs and express higher levels of ABCG2 compared with those without stem cell phenotype (29)(30)(31). The activation of ABCG2 (32) or ABCB1 (31) is considered to be one of the mechanisms for drug resistance of CSCs. For instance, the presence of ABCG2 in certain populations of CSCs increases the likelihood of resistance to various anticancer drugs (33,34).…”

Emetine Synergizes with Cisplatin to Enhance Anti-Cancer Efficacy against Lung Cancer Cells

“…In addition, constitutive Wnt pathway activation is associated with tumor recurrence and poor prognosis in NSCLC patients [9,40,41,42,43,44,45]. The Wnt/β-catenin pathway has also been reported to play a key role in cisplatin resistance in various human cancer types, including lung cancer [46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Cancer stem cells (CSCs) are associated with chemoresistance, and Wnt signaling is one of their regulators [11,13].…”

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

“…The lncRNA HOXA distal transcript antisense RNA (HOTTIP) is strongly connected to cancer and has previously been reported to enhance tumor progression and chemoresistance [179]. Jiang et al [44] were the first to investigate HOTTIP's involvement in PCa chemoresistance. As reported, suppression of HOTTIP resulted in increased cisplatin sensitivity in the PCa cell lines DU-145 and PC-3 by inhibiting Wnt/β-catenin signaling [44].…”

“…Jiang et al [ 44 ] were the first to investigate HOTTIP’s involvement in PCa chemoresistance. As reported, suppression of HOTTIP resulted in increased cisplatin sensitivity in the PCa cell lines DU-145 and PC-3 by inhibiting Wnt/β-catenin signaling [ 44 ]. This corroborates a number of previous studies that found HOTTIP to promote chemoresistance in numerous cancer entities [ 180 , 181 , 182 ], including osteosarcoma in which the regulation of Wnt/β-catenin by HOTTIP was also described [ 182 ].…”

“…This corroborates a number of previous studies that found HOTTIP to promote chemoresistance in numerous cancer entities [ 180 , 181 , 182 ], including osteosarcoma in which the regulation of Wnt/β-catenin by HOTTIP was also described [ 182 ]. However, Jiang et al [ 44 ] did not investigate if other potential effectors such as miRNAs or proteins are involved in the connection between HOTTIP and Wnt/β-catenin regulation and moreover in vivo models are missing.…”