Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

Zhang, Y; Bao, Chunyan; Mu, Quanquan; Chen, J; Wang, J; Mi, Yue; Aj, Sayari; Chen, Y; Guo, Mingzhou

doi:10.4149/304_150806n433

Cited by 52 publications

(36 citation statements)

References 31 publications

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“…Consistent with recent studies associating loss of PER2 with chemoresistance in cancer [17,26,27], we found that SKOV3/DDP cells had dramatically decreased mRNA levels of PER2 compared with parental cells. Previous studies have shown that microRNAs, such as miR-24, miR-449a, and miR-484, inhibit PER2 transcription by binding to its 3'-untranslated region [28,29].…”

Section: Discussionsupporting

confidence: 92%

Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer

Wang

Wei

et al. 2020

Preprint

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Background Circadian clock protein PERIOD2 (PER2) acts as a tumor suppressor in cancer; however, little is known about its involvement in chemosensitivity. Methods This study aimed to investigate the role and underlying mechanisms of PER2 in ovarian cancer sensitivity to cisplatin. Overexpression and knockdown of PER2 were performed to explore its role in ovarian cancer cell sensitivity to cisplatin both in vitro and in vivo. The protein levels of PI3K, AKT, caspase 3, E-cadherin, and other drug resistance-related molecules were determined in parental SKOV3 and SKOV3/DDP cells as well as in xenograft tumor tissues. Results Compared with parental cells, SKOV3/DDP cells had dramatically decreased PER2 expression, possibly due to hypermethylation in the PER2 promoter. PER2 overexpression significantly inhibited proliferation while promoting cisplatin-induced apoptosis in SKOV3 and SKOV3/DDP cells. In agreement, PER2-overexpressing SKOV3/DPP cells yielded significantly reduced tumor mass in cisplatin-treated mice compared with control cells. Mechanistically, PER2 overexpression remarkably reduced the protein amounts of PI3K, AKT, and MDR1, while increasing those of caspase 3 and E-cadherin in tumor tissues. Knockdown of PER2 exhibited opposite effects. PER2 overexpression also reduced the serum levels of TNF-α and IL-6 in tumor-bearing mice before the initiation of cisplatin treatment. Conclusion This study suggests that loss of PER2 contributes to cisplatin resistance in SKOV3 cells, possibly by activating the PI3K/AKT pathway and EMT, inhibiting apoptosis, and promoting drug efflux and inflammatory responses. Overexpression of PER2 could reverse these alterations and sensitize both parental SKOV3 and SKOV3/DDP cells to cisplatin.

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Section: Discussionsupporting

confidence: 92%

Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer

Wang

Wei

et al. 2020

Preprint

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“… 25 Furthermore, activated AKT plays an important role in cisplatin resistance of lung cancer. 26 , 27 Thus, our results lead to the following hypothesis: S100A16 induces the metastatic potential and resistance to platinum-based adjuvant chemotherapy of lung adenocarcinoma through the activation of the AKT signaling pathway. EMT is a process whereby epithelial cells lose polarity and cell–cell adhesion and progress to invasive mesenchymal cells.…”

Section: Discussionmentioning

confidence: 59%

S100A16, a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma

Katono¹,

Sato²,

Kobayashi³

et al. 2017

OTT

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PurposeAlthough cisplatin-based adjuvant chemotherapy improves the survival of patients with resected non-small-cell lung cancer, not all patients show a survival benefit, and some patients experience severe toxicity. Therefore, identifying biomarkers is important for selecting subgroups of patients who may show improved survival with platinum-based adjuvant chemotherapy. S100A16 is thought to play key roles during different steps of tumor progression. The aim of this study was to evaluate the use of S100A16 expression as a prognostic marker in patients with completely resected lung adenocarcinoma receiving platinum-based adjuvant chemotherapy.MethodsS100A16 expression was immunohistochemically studied in 65 consecutive lung adenocarcinoma patients who underwent complete resection and received platinum-based adjuvant chemotherapy. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate the effect of S100A16 expression on disease-free survival (DFS) and overall survival (OS).ResultsS100A16 expression was detected in 26 of the 65 (40.0%) lung adenocarcinoma patients. Although S100A16 expression was not correlated with DFS (P=0.062), it was significantly correlated with OS (P=0.009). In addition, multivariable analysis revealed that S100A16 expression independently predicted a poorer survival (HR =4.79; 95% CI =1.87–12.23; P=0.001).ConclusionThe present study revealed that S100A16 is a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma. A further large-scale study is needed to confirm the present results.

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“…Currently, it is generally believed that PTEN, as the main inhibitor of the PI3K/AKT signaling pathway, can negatively regulate the signaling pathway by dephosphorylating PIP3 to generate PIP2, which results in the downregulation of p-AKT, thus inhibiting the proliferation of cancer cells ( Tay et al, 2011 ; Russell et al, 2018 ). Interestingly, Zhang et al reported that Wortmannin sensitized DDP-resistant human lung cancer cells by downregulating the PI3K/AKT signaling pathway ( Zhang et al, 2016 ), which prompted us to question whether hesperetin could also enhance the sensitivity of GC cells to DDP by inhibiting this pathway. Furthermore, a recent study showed that hesperetin inhibited the PI3K/AKT signaling pathway by upregulating PTEN expression, thus inhibiting cell proliferation ( Li et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Hesperetin Promotes Cisplatin−Induced Apoptosis of Gastric Cancer In Vitro and In Vivo by Upregulating PTEN Expression

Liu

et al. 2020

Front. Pharmacol.

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As one of the most common malignant gastrointestinal tumors, gastric cancer (GC) has a high incidence and poor prognosis. Cisplatin (DDP) is often used as chemotherapy for advanced GC; however, the high incidence of drug resistance remains a problem. The use of several anti-tumor drugs as combined chemotherapy is an effective strategy. Hesperetin has anti-tumor ability via its pro-apoptotic effect on various human cancers, both in vitro and in vivo , with no significant toxicity. However, a combination of DDP and hesperetin in GC has not been reported. The present study aimed to investigate the in vitro and in vivo chemosensitization effect and mechanism of hesperetin-augmented DDP-induced apoptosis of GC. The proliferation of GC ty -60cells was inhibited significantly in a time and dose-dependent manner by combined treatment of DDP with hesperetin. Hesperetin markedly increased DDP-induced apoptosis of GC cell lines. In a xenograft tumor mouse model, markedly better tumor suppression was observed after treatment with DDP plus hesperetin compared with that of either agent alone. Additionally, the combination of DDP and hesperetin remarkably increased the expression levels of phosphatase and tensin homolog (PTEN) and Cytochrome C (Cyt C), and significantly decreased the levels of phosphorylated protein kinase B (p-AKT) and CyclinD1. DDP and hesperetin also induced significant increases in apoptosis inducing factor (AIF), BCL2 associated X, apoptosis regulator (BAX), cleaved caspase-9, and cleaved caspase-3, and decreased B-cell lymphoma 2 (BCL2), caspase-9, and caspase-3 levels. Thus, we demonstrated that hesperetin could inhibit the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling pathway and induce the mitochondrial pathway via upregulating PTEN expression, thereby significantly enhancing DDP’s anti-tumor effect on GC. Hesperetin is a potential chemotherapeutic agent for GC and merits further clinical investigation.

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Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

Cited by 52 publications

References 31 publications

Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer

Circadian Clock Protein PERIOD2 Suppresses the PI3K/Akt Pathway and Promotes Cisplatin Sensitivity in Ovarian Cancer

S100A16, a promising candidate as a prognostic marker for platinum-based adjuvant chemotherapy in resected lung adenocarcinoma

Hesperetin Promotes Cisplatin−Induced Apoptosis of Gastric Cancer In Vitro and In Vivo by Upregulating PTEN Expression

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