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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 362-369

Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy


1 Department of Pharmacy, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
2 Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Date of Submission17-Jun-2021
Date of Acceptance13-Jan-2022
Date of Web Publication06-May-2022

Correspondence Address:
Hongyan Yang
Department of Oncology, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan, Shandong 250013
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_968_21

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 > Abstract 


Aim: This study aimed to explore the role of pantoprazole (PPZ) in affecting the sensitivity of cervical cancer (CC) cells to cisplatin.
Methods: HeLa and CaSki cells were exposed to cisplatin and/or PPZ treatment. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony formation, flow cytometry, wound healing, and transwell assays were performed to detect cell viability, proliferation, apoptosis, migration, and invasion of CC cells, respectively. Then, expressions of Beclin-1, LC3, and p62 were measured by western blot. Rapamycin (Rapa), acting as an autophagy activator, was applied to confirm the effect of autophagy on the sensitivity of CC cells to cisplatin.
Results: Cisplatin treatment suppressed cell viability and proliferation and accelerated apoptosis of CC cells. Combination of cisplatin and PPZ or PPZ alone significantly inhibited cell viability, proliferation, migration, and invasion, and increased cell apoptosis of CC cells. Cisplatin enhanced expression levels of Beclin1 and LC3II/I, and reduced p62 expression. Combination of cisplatin and PPZ significantly decreased the expression levels of Beclin1 and LC3II/I, but increased p62 expression. The autophagy activator, Rapa, eliminated the inhibitory effects of the combination of cisplatin and PPZ on autophagy, and enhanced cell viability, but inhibited apoptosis of CC cells.
Conclusion: PPZ promotes the sensitivity of CC cells to cisplatin by inhibiting cisplatin-induced cell autophagy.

Keywords: Autophagy, cervical cancer, cisplatin sensitivity, pantoprazole


How to cite this article:
Su G, Chen X, Yang H. Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy. J Can Res Ther 2022;18:362-9

How to cite this URL:
Su G, Chen X, Yang H. Pantoprazole promotes the sensitivity of cervical cancer cells to cisplatin by inhibiting cisplatin-induced autophagy. J Can Res Ther [serial online] 2022 [cited 2022 Jul 7];18:362-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/362/344878




 > Introduction Top


Among female cancers, cervical cancer (CC) is a cancertype ranking the fourth in incidence and mortality.[1] In the world, more than 270, 000 women die of CC yearly.[2] So far, the common management for CC patients is surgical resection, chemotherapy, and radiotherapy.[3],[4],[5] However, the occurrence of drug resistance seriously reduces the effectiveness of CC therapy.[6],[7] Therefore, reducing drug resistance and improving drug sensitivity are of great significance for the effective treatment of CC.

Pantoprazole (PPZ) is a proton-pump inhibitor (PPI) that inhibits the gastric H+, K+-ATPase proton pump.[8] Researches have reported that PPIs might inhibit autophagy by inhibiting endosome acidification or fusion with autophagosomes.[9],[10] He et al. have indicated that the PPI esomeprazole can reverse YAP-mediated paclitaxel resistance in the epithelial ovarian carcinoma cells.[11] The use of PPI during chemotherapy for patients with platinum resistant or platinum-refractory ovarian cancer can improve the overall survival rate.[12] Lu et al. have reported that the pretreatment of drug-resistant oral epidermoid carcinoma with PPZ promotes the in vivo and in vitro sensitivity of the cells to vincristine.[13] However, the underlying mechanism of PPZ in CC remains unclear.

Cisplatin is a first-line chemotherapeutic drug widely used clinically in the treatment of cancers.[14],[15] It has been reported that cisplatin shows anticancer activity in many cancers including CC, breast, ovarian, lymphomas, testicular, and head-and-neck cancers.[14],[16] However, the occurrence of cisplatin resistance results in unsatisfactory therapeutic effects of cisplatin on CC.[17] In multivariate analysis of patients with epithelial ovarian cancer, chemotherapy sensitivity was statistically significant with OS.[18] The study of Xu et al. has demonstrated that the increase in levels of autophagy is related to the resistance of CC to cisplatin therapy.[19] Furthermore, Li and Zhang have found that the inhibition of cisplatin-induced autophagy enhances the sensitivity of CC cells to cisplatin.[20] However, the effects of PPZ on the sensitivity of CC to cisplatin need further study.

Herein, the CC cell lines HeLa and CaSki were used to investigate whether PPZ affect the sensitivity of CC cells on cisplatin through inhibiting autophagy. The findings of this study may provide experimental supports for further understanding the sensitivity of PPZ to cisplatin in CC.


 > Methods Top


Cell culture and treatment

Human CC cell lines HeLa and CaSki were purchased from EK-Bioscience (Shanghai, China) and cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS, Thermo Fisher Scientific, Waltham, MA, USA) at 37°C in an incubator with 5% CO2. Cisplatin was purchased from Sigma Aldrich (St. Louis, MO, USA) and dissolved in Dulbecco's Modified Eagle Medium (DMEM, Procell Life Science and Technology Co., Ltd., Wuhan, China). PPZ was purchased from Sigma Aldrich (St. Louis, MO, USA) and dissolved in 0.9% saline. Rapamycin (Rapa) was purchased from Sigma Aldrich (St. Louis, MO, USA) and dissolved in dimethyl sulfoxide.

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay

The cell viability of HeLa and CaSki cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The CC cells were cultured in 5% CO2 incubator at 37°C for 24 h. The medium was mixed with 0.0, 2.5, 5.0, 10.0, 20.0, and 40.0 μM of cisplatin, and the cells were further cultured for 48 h. Subsequently, the cells were incubated with MTT (5 mg/mL) solution for 4 h at 37°C. The absorbance was read using a microplate reader (ELX-800; BioTek, Vermont, USA).

Colony formation assay

The proliferative ability of CC cells was evaluated by colony formation assay. HeLa and CaSki cells were seeded into 6-well plates and cultured in DMEM containing 10% FBS for 2 weeks. Then, the cells were fixed with 4% paraformaldehyde and stained with 0.5% crystal violet solution (Thermo Fisher Scientific, Waltham, MA, USA). The numbers of colonies were subsequently counted under a light microscope (Olympus Corporation, Shenzhen, Guangdong, China).

Apoptosis analysis

The apoptosis of HeLa and CaSki cells was analyzed using the Annexin V-FITC apoptosis detection kit (Thermo Fisher Scientific, Waltham, MA, USA). Cells were seeded into 96-well plates and incubated for 48 h, followed by staining with Annexin V-FITC and propidium iodide in the dark for 15 min. A flow cytometer (BD Biosciences, San Jose, CA, USA) was applied to detect the apoptosis of CC cells.

Wound-healing assay

The migration capability of HeLa and CaSki cells was detected by wound healing assay. HeLa and CaSki cells were plated in 6-well plates and cultured until the cells reached at least 90% confluence. The scratch was made with a pipette tip (200 μL) along the center of the plate. The cells were then further incubated for an additional 48 h. Images of wound closure were acquired at 0 and 48 h using a microscope.

Transwell assay

The invasive capability of HeLa and CaSki cells was detected by transwell assay. HeLa and CaSki cells in serum-free DMEM were seeded in the upper chambers coated with Matrigel (BD, Franklin Lakes, New Jersey, USA), and the media containing 10% FBS was added in lower chambers. After incubation for 48 h, invasion cells were fixed by 4% paraformaldehyde and stained with crystal violet. The number of cells was counted under a microscope.

Western blot assay

The total proteins of CC cells were extracted by lysis buffer. The extracts were centrifugated at 12,000 ×g for 30 min at 4°C. The protein concentration was then detected by BCA kit. The proteins were separated by sodium dodecyl-sulfate polyacrylamide gel electrophoresis, followed by transferring to polyvinylidene fluoride (PVDF) membranes. The membranes were incubated in 5% nonfat milk at 25°C for 2 h, and then incubated with primary antibodies (LC3I, LC3II, Beclin1, and p62 were purchased from Thermo Fisher Scientific, Waltham, MA, USA) at 4°C overnight. After washing with tris-buffered saline with Tween-20 (TBST), the membranes were incubated with secondary antibodies for 1 h. The bands were visualized using enhanced chemiluminescence kit (Santa Cruz Biotechnology, CA, USA) and recorded with Tanon 5200 (Tanon, Shanghai, China).

Statistical analysis

All the data are expressed as the means ± standard deviation. The results were analyzed using SPSS 23.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 7.0 software. (GraphPad, La Jolla, CA, USA) The analysis of variance test was used to assess for statistically significant differences among multiple groups. P < 0.05 was defined as statistically significant.


 > Results Top


Cisplatin inhibited cell viability and proliferation and induced apoptosis of cervical cancer cells

We evaluated the cell viability of HeLa and CaSki cells by MTT assay. The results showed that cisplatin treatment at 2.5–40.0 μM significantly decreased the cell viability of CC cells in a dose-dependent manner [[Figure 1]a, P < 0.05]. The effect of cisplatin on the proliferative ability of HeLa and CaSki cells was detected by colony formation assay. As shown in [Figure 1]b, cisplatin treatment remarkably inhibited the proliferation of CC cells dose-dependently. Besides, we analyzed the effect of cisplatin on apoptosis of CC cells. The data in [Figure 1]c, cisplatin at 2.5–40.0 μM significantly enhanced the apoptotic rates of HeLa and CaSki cells in a dose-dependent manner (P < 0.05).
Figure 1: Cisplatin inhibited cell viability and proliferation, and induced apoptosis of cervical cancer cells. (a) The cell viability of HeLa and CaSki cells treated with cisplatin at 0.0, 2.5, 5.0, 10.0, 20.0, and 40.0 μM was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. (b) The proliferative ability of HeLa and CaSki cells treated with cisplatin at 0.0, 2.5, 5.0, 10.0, 20.0, and 40.0 μM was detected by the colony formation assay. (c) The apoptosis of HeLa and CaSki cells treated with cisplatin at 0.0, 2.5, 5.0, 10.0, 20.0, and 40.0 μM was detected by flow cytometry. *P < 0.05

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Pantoprazole treatment further promoted cisplatin-induced apoptosis of cervical cancer cells

To investigate the effect of PPZ on the CC cells, we determined the cell viability, proliferation, and apoptosis of HeLa and CaSki cells treated with PPZ (160 μg/mL) alone or co-treated with cisplatin (10 μM) and PPZ. As shown in [Figure 2]a, the viability of HeLa and CaSki cells in PPZ group was significantly lower than that in control group (P < 0.05). Compared with cisplatin group, the viability of HeLa and CaSki cells in Cisplatin + PZZ group remarkably decreased [[Figure 2]a, P < 0.05]. The colony formation assay showed that both cisplatin and PPZ significantly suppressed the proliferative ability of HeLa and CaSki cells [[Figure 2]b, P < 0.05]. Besides, PPZ further enhanced the inhibitory effect of cisplatin on proliferative ability of HeLa and CaSki cells [[Figure 2]b, P < 0.05]. The data of flow cytometry showed that the apoptotic rates of HeLa and CaSki cells were markedly decreased by cisplatin and PZZ (P < 0.05), and PZZ further accelerated apoptosis of CC cells induced by cisplatin [[Figure 2]c, P < 0.05].
Figure 2: Treatment with pantoprazole further promoted cisplatin-induced apoptosis of cervical cancer cells. (a) The cell viability of HeLa and CaSki cells treated with cisplatin (10 μM), pantoprazole (160 μg/mL), or co-treated with cisplatin and pantoprazole was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. (b) The proliferative ability of HeLa and CaSki cells treated with cisplatin, pantoprazole, or co-treated with cisplatin and pantoprazole was detected by colony formation assay. (c) The apotosis of HeLa and CaSki cells treated with cisplatin, pantoprazole, or co-treated with cisplatin and pantoprazole was detected by flow cytometry. *P < 0.05 versus control group, #P < 0.05 versus cisplatin group

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Pantoprazole treatment further inhibited cisplatin-induced inhibition in migration and invasion of cervical cancer cells

We examined the effects of cisplatin (10 μM), PPZ (160 μg/mL), and the combination of cisplatin and PPZ on the migration and invasion of HeLa and CaSki cells by wound healing assay and transwell assays, respectively. As shown in [Figure 3]a, both cisplatin and PPZ significantly suppressed the migratory capability of HeLa and CaSki cells in comparison with control group (P < 0.05). The transwell assay showed that cisplatin and PPZ remarkably decreased the number of invasive CC cells compared with control group [[Figure 3]b, P < 0.05]. In addition, we found that the combination of cisplatin and PPZ significantly enhanced the inhibitory effect of cisplatin on migration and invasion of HeLa and CaSki cells (P < 0.05).
Figure 3: Treatment with pantoprazole further inhibited cisplatin-induced inhibition in migration and invasion of cervical cancer cells. (a) The migration capability of HeLa and CaSki cells treated with cisplatin, pantoprazole, or co-treated with cisplatin (10 μM) and pantoprazole (160 μg/mL) was detected by wound healing assay. (b) The invasive capability of HeLa and CaSki cells treated with cisplatin, pantoprazole, or co-treated with cisplatin and pantoprazole was detected by transwell assay. *P < 0.05 versus control group, #P < 0.05 versus cisplatin group

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Pantoprazole inhibited cisplatin-induced autophagy in cervical cancer cells

Researches have indicated that cisplatin can induce autophagy in cancer cells.[21],[22] To measure the autophagy of HeLa and CaSki cells after treatment with cisplatin (10 μM) and/or PPZ (160 μg/mL), the expression levels of LC3, Beclin1, and p62 were assessed by western blot. The results in [Figure 4]a and [Figure 4]b display that cisplatin markedly increased the protein expression of Beclin1 and LC3II/I, and decreased p62 protein expression (P < 0.05). Conversely, the protein expression levels of Beclin1 and LC3II/I in PZZ group were significantly lower than that in the control group, and p62 expression levels were markedly higher than that in the control group [[Figure 4]a and [Figure 4]b, P < 0.05]. Besides, combination of cisplatin and PPZ significantly reduced the protein levels of Beclin1 and LC3II/I, and enhanced the p62 protein levels inhibited by cisplatin [[Figure 4]a and [Figure 4]b, P < 0.05].
Figure 4: Treatment with pantoprazole inhibited cisplatin-induced autophagy in cervical cancer cells. (a) The protein expression of LC3, Beclin1, and p62 in HeLa cells treated with cisplatin (10 μM), pantoprazole (160 μg/mL), or co-treated with cisplatin and pantoprazole was detected by western blot. (b) The protein expression of LC3, Beclin1, and p62 in CaSki cells treated with cisplatin, pantoprazole, or co-treated with cisplatin and pantoprazole was detected by western blot. *P < 0.05 versus control group, #P < 0.05 versus cisplatin group

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PZZ promoted cisplatin-induced apoptosis of cervical cancer cells through inhibiting autophagy

To further verify the inhibitory effect of PPZ (160 μg/mL) on cisplatin-induced autophagy in CC cells, an autophagy activator rapamycin (Rapa, 50 nM), was used to culture HeLa and CaSki cells. After Rapa treatment, we determined detected the protein expression of Beclin1, LC3, and p62 in CC cells using western blot. As shown in [Figure 5]a and [Figure 5]b, PPZ significantly reduced the protein expression of Beclin1 and LC3II/I induced by cisplatin, while the inhibitory effect of PPZ on expression levels of Beclin1 and LC3II/I was significantly eliminated by the autophagy activator Rapa (P < 0.05). The p62 protein expression in Cisplatin + PPZ + Rapa group was remarkably decreased compared with Cisplatin + PPZ group (P < 0.05). Results of western blot showed that the combination of cisplatin and PPZ significantly decreased the p62 expression levels (P < 0.05). However, activation of autophagy eliminated the effect of PPZ on p62 protein expression (P < 0.05). The viability of HeLa and CaSki cells was increased in Cisplatin + PPZ + Rapa group compared with Cisplatin + PPZ group [[Figure 5]c and [Figure 5]d, P < 0.05]. The flow cytometry data showed that activation of autophagy weakened the inhibitory effect of the combination of cisplatin and PPZ on apoptosis of HeLa and CaSki cells [[Figure 5]e and [Figure 5]f, P < 0.05].
Figure 5: Pantoprazole promoted cisplatin-induced apoptosis of cervical cancer cells via inhibition of autophagy. (a and b) The protein expression of LC3, Beclin1, and p62 in HeLa and CaSki cells treated with autophagy activator rapamycin (Rapa, 50 nM) was detected by western blot. (c and d) The viability of HeLa and CaSki cells treated with Rapa was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. (e and f) The apoptotic rates of HeLa and CaSki cells treated with Rapa was detected by flow cytometry. *P < 0.05 versus control group, #P < 0.05 versus cisplatin group, and P < 0.05 versus cisplatin + pantoprazole group

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 > Discussion Top


CC is a common female cancer, which is a significant threat to women's health.[23] Although advanced treatments, including surgery, radiotherapy, and chemotherapy have improved the overall survival rates, the prognosis and 5-year overall survival rate of patients with CC remains poor due to the emergence of drug resistance.[24] In our study, we found that cisplatin inhibited cell viability, proliferation ability, migration and invasion, and induced apoptosis and autophagy of CC cells. The combination of cisplatin and PPZ significantly inhibited cisplatin-induced autophagy in CC cells. PPZ treatment further reduced cell viability and increased apoptosis in CC cells. The effects of PPZ on the sensitivity of CC cells to cisplatin could be eliminated by treatment with the autophagy activator, Rapa.

Cisplatin is one of the most stable and popular of platinum drugs in clinical therapy for human cancer.[14] A large number of studies have proved that cisplatin exhibits cytotoxic effect in cancer cells.[25],[26] Cisplatin treatment inhibits cell proliferation and induces cell apoptosis in non-small cell lung cancer.[27] A previous study found that cisplatin can reduce viability of osteosarcoma cells.[28] Hassanvand et al. found that cisplatin induced apoptosis in human breast cancer cells.[29] Researches have indicated that cisplatin facilitates apoptosis of CC cells and inhibits the progression of CC.[30],[31] The data in this study showed that cisplatin treatment significantly decreased cell viability and proliferation and accelerated apoptosis of CC cells. Besides, we found that cisplatin induced cell autophagy in CC cells. The expression levels of Beclin1 and LC3II/I were increased, and p62 protein was decreased in cisplatin-treated CC cells.

Autophagy is a complex, stepwise process involving numerous protein complexes encoded by different evolutionarily conserved autophagy-related genes.[32] Autophagy usually helps to promote cell survival in the case of nutritional deficiency. Relying on this process, cancer cells grow and thrive in a harsh and nutrient-depleted tumor microenvironment.[33] The study of Fu et al. has found that inhibition of autophagy arrests the growth of colorectal cancer cells both in vitro and in vivo.[34] The findings of Zhang et al. have suggested that induction of autophagy enhances the resistance of ovarian cancer cells to paclitaxel.[35] In this study, we found that the combination of cisplatin and PPZ remarkably suppressed autophagy and facilitated apoptosis induced by cisplatin. Combination of cisplatin and PPZ or PPZ alone significantly decreased the expression of Beclin1, LC3II/I, and increased p62 protein expression. The cell viability, proliferation, migration, and invasion were reduced by PPZ treatment or combination of cisplatin and PPZ. These data suggested that PPZ might accelerate cisplatin induced apoptosis and inhibited proliferation, migration, and invasion of CC cells via the inhibition of cell autophagy.

Subsequently, we supplemented with the autophagy activator, Rapa, in the experiment to further confirm whether PPZ enhanced the sensitivity of CC cells to cisplatin by inhibiting autophagy induced by cisplatin. The results showed that Rapa significantly increased the protein expressions of Beclin1 and LC3II/I suppressed by PPZ. Activation of autophagy decreased p62 levels that were increased by PPZ. Additionally, we found that Rapa significantly enhanced the cell viability of HeLa and CaSki cells which were inhibited by the combination of cisplatin and PPZ. The apoptotic rate of CC cells was dramatically reduced by the autophagy activator Rapa. These results were in line with other researches. For instance, the work of Zhao and Xia has indicated that the inhibition of cisplatin-induced autophagy significantly increased cell apoptosis whereas activating autophagy significantly decreased apoptosis of ovarian carcinoma cells.[36] Jiang et al. have demonstrated that the autophagy inhibitor, 3-methyladenine alleviated the sensitivity of CC cells to cisplatin in vivo and promoted the growth of tumor tissues.[37] These data confirmed that inhibition of cell autophagy was vital to PPZ-accelerated apoptosis of CC cells.


 > Conclusion Top


We confirmed the promoting effects of PPZ on the cisplatin sensitivity of CC cells in vitro. Combination of cisplatin and PPZ reduced cell viability and facilitated apoptosis of CC cells. We found that PPZ elevated the sensitivity of CC cells to cisplatin via inhibition of cisplatin-induced autophagy. Activation of autophagy eliminated the promoting effects of combination of cisplatin and PPZ on sensitivity of CC cells to cisplatin. We considered that PPZ might be a chemo-sensitizer by enhancing the apoptosis of cisplatin-treated CC cells. However, more in vivo studies are still needed in the future to confirm our speculations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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