Cotargeting Plk1 and androgen receptor enhances the therapeutic sensitivity of paclitaxel-resistant prostate cancer

Abstract

Backgrounds: Despite the clinical success of taxanes, they still have limitations, such as chemoresistance. To overcome the limitations of paclitaxel, genetic alterations and targeting effects of altered genes were observed in paclitaxel-resistant cancer. Because paclitaxel-resistant cancer shows high levels of Plk1, a promising target in chemotherapy, the effectiveness of Plk1 inhibitors in paclitaxel-resistant cancer cells has been investigated. Methods: Paclitaxel-resistant cancer cells were developed by exposure of stepwise escalating levels of paclitaxel. Genetic alterations were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblotting. Using a cell viability assay, combined targeting effects for Plk1 and androgen receptor (AR) were determined. Clinical data were analyzed to understand the relationship between Plk1 and AR in prostate cancer patients. Results: Treatment with Plk1 inhibitors markedly reduced the expression of MDR1, MRP1, and Plk1 in the paclitaxel-resistant cancer. Among Plk1 inhibitors, genistein, recently found as a direct Plk1 inhibitor, tended to be more effective in the paclitaxel-resistant prostate cancer than the parental cancer cells, which was related to the suppression of the AR, as well as inhibition of Plk1 activity. A combination of Plk1 inhibitors and AR antagonist bicalutamide exhibited a synergistic effect in LNCaP TXR , as well as LNCaP cells, by inhibiting Plk1 and AR. Analysis of clinical data provides evidence for the relevance between Plk1 and AR in prostate cancer patients, showing that Plk1 and AR are strong predictors of poor survival rates. Conclusions: We suggest that cotargeting Plk1 and AR would be effective in advanced chemoresistant prostate cancer cells to overcome the limitations associated with paclitaxel.

Immune-related biomarker risk score predicts prognosis in prostate cancer

“…The role of PLK1 in prostate cancer is not clear at present [ 23 ]. However, numerous studies indicate that PLK1 can act as an oncogene, and PLK-1 inhibitors can effectively inhibit prostate cancer progression [ 24 – 26 ]. PLK1 can also inactivate other tumor suppressors [ 27 , 28 ].…”

Molecular Mechanisms of Action of Genistein in Cancer: Recent Advances

“…Polo-like kinase 1 (Plk1) has been shown to be involved in chemoresistance, so Plk1-targeted therapies could possibly reduce or eliminate the chemoresistance of cancer cells against anticancer drugs. Genistein was proposed as a Plk1 inhibitor, which effectively downregulates the expression of multidrug resistance protein 1 and multidrug resistance-associated protein 1, key factors inducing chemoresistance in paclitaxel-resistant cancer cells (Shin et al, 2019). The discovery of genistein being a Plk1 inhibitor adds a new horizon for the possible application of genistein as adjuvant in chemotherapy because of its ability to prevent cancer cells from acquiring resistance against the anticancer drugs or due to resensitize drug-resistant cancer cells.…”

Combination of Inhibitors of USP7 and PLK1 has a Strong Synergism against Paclitaxel Resistance

“…Previous studies have revealed that PLK1 is highly expressed in several malignancies, and that PLK1 is involved in chemoresistance [ 30 , 31 ]. Moreover, PLK1 is highly expressed in paclitaxel-resistant prostate and lung cancer [ 30 ].…”

“…Previous studies have revealed that PLK1 is highly expressed in several malignancies, and that PLK1 is involved in chemoresistance [ 30 , 31 ]. Moreover, PLK1 is highly expressed in paclitaxel-resistant prostate and lung cancer [ 30 ]. To investigate the possibility of improving the efficacy of current treatment regimens for paclitaxel-resistant lung cancer, a paclitaxel-resistant lung cancer cell line was co-treated with the PLK1 inhibitor volasertib combined with the USP7 inhibitor P22077 ( Figure 5 ).…”

“…Therefore, combination therapy has been recently investigated to overcome this barrier to effective treatment. Previously, we found that PLK1 is highly expressed in taxane-resistant prostate and lung cancer [ 30 ]. In addition, we observed that PLK1 inhibition is effective in suppressing the growth of taxane-resistant prostate cancer cells by causing mitotic aberration [ 30 ].…”