The role of the <i>SHH</i> gene in prostate cancer cell resistance to paclitaxel

Statkiewicz, Małgorzata; Maryan, Natalia; Lipiec, Agnieszka; Grecka, Emilia; Grygorowicz, Monika Anna; Omiotek, Marcin; Górska, Agnieszka; Mikula, Michał; Małecki, Maciej

doi:10.1002/pros.22830

Cited by 22 publications

(21 citation statements)

References 44 publications

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“…Downregulation of CTEN mediates paclitaxel resistance through increasing expression of EGFR and actin (13). Overexpression of Sonic Hedgehog (SHH) increases PCa cell resistance to paclitaxel and leads to increase in ATP-binding cassette (ABC) transporters expression (14,15). Recently, it has been reported that Sex determining region Y-box 2 (Sox2) is involved in paclitaxel resistance of PC-3-TxR cells via the PI3K/Akt pathway (16).…”

Section: Discussionmentioning

confidence: 99%

Skp2 is associated with paclitaxel resistance in prostate cancer cells

et al. 2016

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Prostate cancer is the most commonly diagnosed tumor in men in the United States. Patients with hormone-refractory prostate cancer are often treated with paclitaxel, but most of them eventually develop drug resistance. S-phase kinase associated protein 2 (Skp2) is a component of the SCF (Skp1-Cullin1-F-box) type of E3 ubiquitin ligase complexes. In the present study, we investigated the role of Skp2 in paclitaxel-resistant DU145-TxR or PC-3-TxR cells by Skp2 silencing or using Skp2 inhibitors. We first confirmed that Skp2 expression is up-regulated in DU145-TxR or PC-3-TxR cells compared with their parental cells DU145 or PC-3, respectively. Knockdown of Skp2 or Skp2 inhibitor treatment in DU145-TxR or PC-3-TxR cells restored paclitaxel sensitivity. E-cadherin was decreased while Vimentin was increased in PC-3-TxR or DU145-TxR cells. In addition, p27 expression was inversely correlated with Skp2 expression in DU145-TxR or PC-3-TxR cells. Moreover, p27 was found to increase in both Skp2 silencing PC-3-TxR and DU145-TxR cells. These results suggest that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 may be a potential therapeutic target for drug-resistant prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Skp2 is associated with paclitaxel resistance in prostate cancer cells

et al. 2016

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“…A previous study indicated that overexpressing SHH increased drug resistance in prostate cancer cells and enhanced the expression of ABC transporters. 5 Another report revealed the detectable interaction between SHH-GLI1-ABCG2 pathway and drug resistance in ovarian cancer. 22 As a downstream molecule of SHH signaling pathway, ABCB2 contributes to the drug resistance of pancreatic ductal adenocarcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…4 Multidrug resistance (MDR) is a phenomenon in which cancer cells exhibit a cross-resistant phenotype against multiple unrelated chemotherapy drugs with complex mechanisms. 5 The MDR mechanism in tumors has been reported to include upregulated ATP-binding cassette (ABC) transporters, elevated apoptotic thresholds, abnormal vasculature, increased interstitial fluid pressure, and numerous other factors that led to the reduction or removal of chemotherapeutic agents. 6 Studies of MDR have mainly focused on increasing the efflux of drugs, decreasing the absorption of drugs, blocking the induction of the apoptosis by most anticancer drugs, activating DNA damage repair, and inactivating antineoplastic drugs.…”

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confidence: 99%

Hedgehog signaling promotes multidrug resistance by regulation of ABC transporters in oral squamous cell carcinoma

Wang

Huang

et al. 2020

J Oral Pathology Medicine

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Background: Multidrug resistance (MDR) is one of the reasons for treatment failure in oral squamous cancer patients; however, the MDR mechanisms remain elusive. Methods: Two human oral squamous cell carcinoma (OSCC) cell lines, CAL27 and SCC9, were analyzed by stepwise selection upon exposure to 5-fluorouracil (5-FU) and cisplatin (CDDP) for MDR cell line establishment, and cell viability was analyzed by CCK8 assays. Transcriptomes of the CAL27 and CAL27-MDR cells were analyzed by RNA-seq assay. The molecules in Sonic hedgehog (Shh) signal pathway and MDR related pathway were selected for validation by qRT-PCR and Western blot. Human OSCC tissues were applied for immunohistochemical and clinicopathological analysis. Results: The OSCC-MDR cell lines with resistance to 5-FU and CDDP were successfully established. Protein expression levels of ATP-binding cassette (ABC) transporter ABCC1 and ABCG2 were increased 1.6-fold and 2.1-flod, respectively, in OSCC specimen from the patients with chemotherapy. The RNA-seq assay speculated the activation of Hedgehog (Hh) signaling with the upregulation of SHH, PTCH1, and SMO in OSCC-MDR cells as compared with OSCC cells. Furthermore, immunohistochemical studies confirmed that the high expression of SHH, PTCH1, and SMO in OSCC patients was significantly associated with chemotherapy. Overexpression of SHH increased the chemoresistance in OSCC cells, while the mRNA expression levels of PTCH1 and ABCG2 were increased in OSCC cells upon stimulation with recombinant SHH protein. Conclusions: These results revealed that the activation of Hh signaling pathway regulating ABC transporters is associated MDR in OSCC.

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“…This result was consistent with a previous study, which reported that Shh was detected in cultured cancer cell media. 33 We also studied the relationship between the expression of Shh and AR. First, we divided cancer patients into the AR-positive (AR + ) and AR-negative (AR − ) groups.…”

Section: Discussionmentioning

confidence: 99%

<p>Shh Overexpression Is Correlated with GRP78 and AR Expression in Primary Prostate Cancer: Clinicopathological Features and Outcomes in a Chinese Cohort</p>

Zhang

Lin

et al. 2020

CMAR

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These authors contributed equally to this work Introduction: Shh plays an important role in prostate cancer progression, but its correlation with GRP78 and AR is elusive. Methods: The study included 539 patients in total, of which 443 had primary prostate carcinoma and 96 patients had benign prostatic hyperplasia (BPH). The clinicopathologic features, histologic scores of protein expression, and correlations between protein and disease state were studied in this cohort. Kaplan-Meier and Pearson correlation analyses were used to compare measures between groups. We performed immunohistochemistry to evaluate the expression of the Shh protein in benign prostatic hyperplasia (n=96) and prostate cancer (Gleason scores ≤6 [n=399] or ≥7 [n=44]). We quantified the expression of Shh, AR, and GRP78 using the weighted histoscore method, studied the correlation between Shh expression and AR and GRP78, and evaluated the impact of Shh protein expression on patient survival. Results: Shh expression was significantly higher in prostate cancer with Gleason scores ≥7 than in cancer with lower Gleason scores or benign hyperplasia and was much higher in ARpositive cancer than in AR-negative cancer. Shh is overexpressed in high-grade prostate cancer and is positively correlated with the expression of both GRP78 and AR. Conclusion: Therefore, Shh may be a useful prognostic marker and therapeutic target for prostate cancer.

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The role of the SHH gene in prostate cancer cell resistance to paclitaxel

Abstract: Overexpression of SHH enhances PCa cell lines resistance to paclitaxel. Higher level of SHH leads to increase in ABC transporters expression in a manner dependent on paclitaxel.

Cited by 22 publications

References 44 publications

Skp2 is associated with paclitaxel resistance in prostate cancer cells

Skp2 is associated with paclitaxel resistance in prostate cancer cells

Hedgehog signaling promotes multidrug resistance by regulation of ABC transporters in oral squamous cell carcinoma

<p>Shh Overexpression Is Correlated with GRP78 and AR Expression in Primary Prostate Cancer: Clinicopathological Features and Outcomes in a Chinese Cohort</p>

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