Correlation Study on the Expression of INSR, IRS-1, and PD-L1 in Nonsmall Cell Lung Cancer

Ting, Ma; Miao, Yu-e; Yu, Feng-xiu; Luo, Guang-cai; Xu, Xin; Xiao, Li-xia; Zhang, Guo-qing; Chang, Jin

doi:https://doi.org/10.1155/2022/5233222

Journal of Oncology

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

The Role of Lipid Metabolism in Tumor Progression

View this Special Issue

Research Article | Open Access

Volume 2022 | Article ID 5233222 | https://doi.org/10.1155/2022/5233222

Correlation Study on the Expression of INSR, IRS-1, and PD-L1 in Nonsmall Cell Lung Cancer

Ma Ting,^1,2Yu-e Miao,³Feng-xiu Yu,⁴Guang-cai Luo,⁵Xin Xu,⁵Li-xia Xiao,²Guo-qing Zhang,⁵and Jin Chang⁵

Academic Editor: Ningke Ruan

Received02 Jul 2022

Revised05 Aug 2022

Accepted11 Aug 2022

Published04 Oct 2022

Abstract

Objective. To study the expression and correlation of insulin receptor (INSR), insulin receptor substrate-1 (IRS-1), and programmed cell death ligand-1 (PD-L1) in nonsmall cell lung cancer (NSCLC). Methods. 45 lung cancer tissues and 30 adjacent normal tissues of NSCLC patients diagnosed in the Second Affiliated Hospital of Shandong First Medical University from June 2019 to August 2020 were selected. The expressions of INSR, IRS-1, and PD-L1 proteins in tumor tissues and adjacent tissues of NSCLC were detected by immunohistochemical staining. Results. The expression of INSR and IRS-1 in NSCLC was significantly higher than that in adjacent normal lung tissue (). INSR expression had statistical significance with the degree of pathological differentiation of nonsmall cell carcinoma (), but had no significant association with age, gender, pathological type, TNM stage, and lymph node metastasis status (). There was no significant correlation between IRS-1 positive expression and NSCLC patients’ age, gender, pathological typing, degree of differentiation, TNM stage, and lymph node metastasis (). PD-L1 positive expression was correlated with lymph node metastasis of NSCLC (), while there was no significant correlation with gender, age, pathological type, TNM stage, and pathological differentiation degree of NSCLC patients (). Spearman correlation analysis showed that PD-L1 protein expression had a significant positive correlation with IRS-1 protein expression (), but was not correlated with the expression of INSR protein. Conclusion. IRS-1 may be involved in the regulation of PD-L1 expression and mediate the occurrence of tumor immune escape, which is expected to become a new target for NSCLC immunotherapy and provide new clinical evidence for immunosuppressive therapy.

1. Introduction

Lung cancer is a common malignant tumor in the world. According to the latest data released by the international agency for research on cancer in CA:A Cancer Journal for Clinicians [1], there were 2.207 million new lung cancer cases and 1.796 million reported deaths worldwide, accounting for 11.7% and 18.0% of the global cancer incidence rate and mortality, respectively. Nonsmall cell lung cancer (NSCLC) has decreased in incidence overall in the past decade in the United States but the incidence of stage I NSCLC has increased along with its prevalence [2], highlighting the need for research in this area. Surgical resection can be the first choice for the treatment of NSCLC. However, more than 70% of patients with NSCLC were often accompanied by tumor proliferation and metastasis and lost the best opportunity for surgery due to the limitations of early diagnosis [3]. According to a global cancer detection report, lung cancer patients in most countries had a 5-year survival rate of only 10-20% [4]. With the continuous development of cancer treatment methods and technologies, the situation has improved [5]. But the problems of drug resistance and immunotoxicity cannot be ignored. Therefore, seeking new treatment targets and exploring their related mechanisms in the occurrence and development of lung cancer are the current research focus and urgent problem to be solved. Therefore, seeking new treatment targets and exploring their related mechanisms in the occurrence and development of lung cancer are the current research focus and urgent problem to be solved.

INSR and IRS-1 can mediate tumorigenesis and development as key mediators in the insulin signal transduction pathway, but their specific biological roles have not been fully clarified. Zhang et al. [6] found that downregulation of INSR can inhibit tumor cell proliferation, angiogenesis, lymphangiogenesis, and metastasis. Kim et al. [7] studied the effect of INSR expression on the survival of patients with NSCLC for the first time and found that INSR expression could be used as an independent prognostic factor for OS and RFS in patients with surgically resected early NSCLC. INSR has been proved to be abnormally expressed in a variety of tumor tissues, such as breast cancer, lung cancer, and gastric cancer [7–9]. Li et al. [10] first found that overexpression of IRS-1 can promote the malignant transformation of mouse embryonic fibroblasts. Subsequently, Tanaka et al. [11] further confirmed that IRS-1 overexpression can induce malignant transformation and proliferation of NIH3T3 fibroblasts by activating ERK1/2 pathway under low serum conditions. In addition, fibroblasts transfected with IRS can form colonies in soft agar, which is also highly tumorigenic when injected into nude mice. As a transmembrane protein, PD-L1 is considered to be an inhibitor of immune responses. It can combine with PD-1 to mediate the occurrence of tumor immune evasion [12]. With the approval of immune checkpoint inhibitors (ICIS), the treatment of immune checkpoints based on regulating PD-1/PD-L1 signaling pathway provides more options for the treatment of patients with advanced NSCLC [13, 14]. Gene expression studies indicate that PD-L1 expression is a biomarker of improved survival and response to immune checkpoint blockade therapy [15, 16]. IRS-1 expression is also associated with prognosis [17].

However, there are few reports on the correlation between INSR, IRS-1, and PD-L1 in NSCLC patients. Therefore, it is of great significance to explore the correlation between the expression levels of INSR, IRS-1, and PD-L1 and reveal the potential mechanism of insulin pathway-related receptors in the occurrence and development of lung cancer.

2. Materials and Methods

2.1. Tissue Samples

45 patients with NSCLC diagnosed in the Second Affiliated Hospital of Shandong First Medical University from June 2019 to August 2021 were selected. The 45 patients with nonsmall cell lung cancer, including 26 males and 19 females, did not receive radiotherapy, chemotherapy, and other antitumor treatments before surgery. The clinical data of all patients included in the experiment were complete, and the postoperative pathology had confirmed NSCLC. The TNM stage was determined according to the 2018 AJCC staging guidelines. This experiment has been approved by the medical ethics committee of our hospital before it is started.

2.2. Immunohistochemistry

The expression of INSR, IRS-1, and PD-L1 in 45 NSCLC tissues and 30 adjacent normal tissues were detected by immunohistochemistry (IHC). The results of immunohistochemical staining were determined by two pathologists using semiquantitative analysis method. The positive staining of INSR was localized in the cell membrane and cytoplasm, while the positive staining of IRS-1 was localized in the cytoplasm and nucleus. Observed the staining intensity and count the proportion of positive cells under a high power microscope. The intensity of the immunostaining was scored as follows: (a) no staining, 0; (b) pale yellow, 1; (c) brown-yellow, 2; and (d) brown, 3. The percentage of positive tumor cells was scored as (a) <5%, 0; (b) 5-25%, 1; (c) 26-50%, 2; (d) 51-75%, 3; and (e) >75%, 4. The two scores were multiplied to produce a weighted score for each case. Cases with weighted scores of more than 3 were defined as positive; otherwise; they were defined as negative. The positive staining of PD-L1 was mainly localized in the cell membrane, which was scored according to the proportion of tumor pigmented cells (TPS Score). When , it was defined as positive, otherwise, it was defined as negative.

2.3. Statistical Analysis

SPSS26.0 statistical software was used for data processing, and the comparison between positive expression rate, expression of each indicator, and clinicopathological data among groups was performed by chi-square test; the correlation between INSR, IRS-1, and PD-L1 expression was tested by Spearman rank correlation analysis. When the default , the difference was considered statistically significant.

3. Results

3.1. Expression of INSR and IRS-1 in NSCLC and Adjacent Normal Tissues

The expression of INSR and IRS-1 in 45 cases of nonsmall cell lung cancer and 30 cases of adjacent normal lung tissues was detected by immunohistochemical staining (Figure 1). The results showed that INSR and IRS-1 are expressed in both lung cancer and adjacent normal tissues. The expression of INSR was dramatically higher in 29 (64.4%) cases compared with 11 (36.7%) cases in adjacent normal tissues (, ). IRS-1 expression was positive in 26 (57.8%) lung cancer tissues, which was significantly higher than 10 (33.3%) cases in adjacent tissues (, ) (Table 1).

(a)

(b)

(c)

(d)

(e)

(f)

(g)

(h)

Figure 1

Representative immunohistochemical staining images of INSR, IRS-1, and PD-L1 in NSCLC tissues and adjacent normal tissues. (Original magnification: ×200). (a) Positive expression of INSR in NSCLC tissues. (b) Negative expression of INSR in NSCLC tissues. (c) Negative expression of INSR in adjacent normal tissues. (d) Positive expression of IRS-1 in NSCLC tissues. (e) Negative expression of IRS-1 in NSCLC tissues. (f) Negative expression of IRS-1 in adjacent normal tissues. (g) Positive expression of PD-L1 in NSCLC tissues. (h) Negative expression of PD-L1 in NSCLC tissues.

3.2. The Relationship between INSR, IRS-1 Expression, and Clinicopathological Features in NSCLC

The results of statistical analysis showed that the positive expression of INSR was correlated with the degree of pathological differentiation of NSCLC patients, and the difference was statistically significant (). There was no correlation with age, gender, pathological type, TNM stage, and lymph node metastasis status (). There was no significant correlation between the positive expression of IRS-1 and NSCLC patients’ age, gender, pathological typing, degree of differentiation, TNM stage, and lymph node metastasis () (Table 2).

3.3. The Relationship between PD-L1 Expression and Clinicopathological Features in NSCLC

There were 24 patients with positive expression, including 6 patients with high expression of PD-L1 () and 18 patients with low expression of PD-L1 () (Figure 1). The results of statistical analysis showed that the positive expression of PD-L1 protein was correlated with lymph node metastasis (), while there was no significant correlation with gender, age, pathological type, TNM stage, and pathological differentiation degree of NSCLC patients () (Table 3).

3.4. Correlation between INSR and PD-L1 Expressions in NSCLC

Spearman rank correlation was used to analyze the correlation between INSR, IRS-1, and PD-L1 expressions in nonsmall cell lung cancer. The results showed that there was no correlation between the expression of INSR and PD-L1 in nonsmall cell lung cancer (, ) (Table 4). There was a positive correlation between the expression of IRS-1 and PD-L1 in nonsmall cell lung cancer (, ) (Table 5).

4. Discussion

The reprogramming of tumor energy metabolism is considered to be one of the typical features of cancer, which endows tumor cells with the potential to continue to grow and proliferate in the tumor microenvironment (TME) with nutrient deficiency [18, 19]. As early as 1924, Ott Warburg first observed this abnormality of energy metabolism of tumor cells. Even in the case of sufficient oxygen supply, tumor cells still prefer to change their metabolic dependence from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis to generate energy [20]. After that, Zhou et al. [21] also found that drug-resistant cell lines have higher levels of aerobic glycolysis capacity, suggesting that there is a biochemical link between drug resistance and glycolysis. Oronsky et al. [22] further proposed that ATP produced by intracellular metabolism is the key determinant of chemoradiotherapy resistance. Controlling the metabolic process in vivo to limit ATP level can improve chemoradiotherapy sensitivity. In conclusion, energy metabolism reprogramming plays an important role in tumorigenesis and development. Therefore, targeted intervention on glycolysis has brought a new idea for tumor treatment, and the relevant studies have also confirmed the effectiveness of this treatment method [23]. Glucose transmembrane transport is considered as the rate limiting step of glycolysis [24]. In order to make up for the low efficiency of glycolysis energy production, tumor cells tend to ingest glucose at a higher rate, which is mediated by glucose transporters (GLUTs). As a transmembrane protein, gluts are widely distributed in human tissues. Up to now, 14 glut subtypes (Glut 1-14) have been found. Gluts, especially Glut1/3, have been observed to be highly expressed in a variety of different types of tumors, such as lung cancer and pancreatic cancer. Its overexpression not only significantly enhanced glucose uptake but also showed a close relationship with the poor tumor prognosis [24–26]. Small molecule inhibitors targeting gluts, including phloretin, WZB117, and STF-31, had also shown good effects in antitumor therapy [27, 28]. Studies have shown that phosphoinositide-3 kinase (PI3K/AKT) and other pathways are central regulators of glycolysis, tumor metabolism, and cancer cell proliferation [29]. In tumor cells, PI3K/AKT pathway can induce the expression of gluts and enhance the glycolysis process [30–33]. In addition, PI3K-Akt pathway is also a classical insulin downstream signaling pathway. In the insulin signaling pathway, when insulin binds to the INSRs on the cell membrane, it enhances the binding affinity between the receptor and IRS protein, causing the phosphorylation of IRSs to be activated. Then, IRSs can activate this pathway by recruiting and activating PI3K. Therefore, we have reason to believe that INSR and IRS-1 are involved in the process of glycolysis metabolism and play an important role in maintaining the survival and proliferation of tumor cells. They are expected to become potential targets for antitumor therapy. Our studies also showed that the positive rate of INSR and IRS-1 protein expression in NSCLC tissues was significantly higher than that in adjacent normal tissues (), suggesting that the expression of they may be involved in the occurrence and development of nonsmall cell lung cancer, which further verified our hypothesis. Heckl et al. have shown that PI3K-Akt pathway activation by insulin serves as an oncogenic driver for the development of NSCLC [34], which supports the investigation of insulin signaling pathways. Furthermore, insulin also acts to induce PD-L1 in pancreatic cancer, and while its role in NSCLC is not directly experimentally verified, it suggests a need to investigate insulin signaling and PD-L1 in NSCLC [35]. In the present study, tissue differentiation was significantly associated with INSR, while lymph node metastasis was linked to PD-L1.

PD-L1 is a recognized immunosuppressive molecule. Tumor cells can negatively regulate the activity of T cells by increasing the expression of PD-L1 on the cell surface, so as to achieve the occurrence of immune escape. With the approval of immune checkpoint inhibitor, immunotherapy against PD-L1 has shown good therapeutic effect in nonsmall cell lung cancer, but its immune-related adverse toxicity cannot be ignored. Therefore, looking for new targets to specifically regulate PD-L1 expression will help to more accurately block tumor-related PD-1/PD-L1 pathway and reduce adverse immune reactions. Previous studies have shown that PI3K/AKT pathway activation can promote PD-L1 expression by increasing exogenous signals or reducing the expression of negative regulatory factors such as PTEN [36]. Zhao et al. [37] confirmed that PD-1/PD-L1 blockade may inhibit the apoptosis of CD8+ T cells in gastrointestinal stromal tumors (GIST) by regulating PI3K/Akt/mTOR pathway. Stutvoet et al. [38] showed that inhibition of MAPK pathway can regulate EGF- and IFN-induced PD-L1 expression in lung adenocarcinoma. These results all suggest that the expression of PD-L1 can be regulated by PI3K/AKT and MAPK signaling pathway. These two pathways happen to be the most important downstream pathways of INSR and IRS-1. Whether they can regulate the abnormal expression of PD-L1 through these pathways has not been clarified yet. IRS proteins play a key role in tumor metabolism by regulating signaling of INSR. However, IRS-1 is also ubiquitously expressed in cancer cells. The differential expressions of IRS-1 versus IRS-2 may regulate drug responses. Further studies are essential to clarify complex signaling mechanisms [39]. Therefore, we used spearman correlation analysis to explore the relationships between them. The result showed that there is a positive correlation between the expression of IRS-1 and PD-L in NSCLC tissues (). Therefore, we speculate that IRS-1 may participate in the expression regulation of PD-L1 and mediate the immune escape process of NSCLC. However, the specific regulatory mechanism between IRS-1 and PD-L1 needs to be further explored in the follow-up study. At the same time, clinical studies with larger sample sizes are essential to understand the specific disease characteristics and prognosis concerning this regulatory axis. The present study utilized IHC alone, and studies at gene, mRNA, and protein expression levels are essential.

5. Conclusion

INSR and IRS-1 are both overexpression in lung cancer tissues, and IRS-1 expression had a significant positive correlation with PD-L1 expression. The expression of IRS-1 may further mediate the occurrence of tumor immune escape. Therefore, a better understanding of the regulatory mechanism of IRS-1 on PD-L1 expression will help to find new targets for NSCLC immunotherapy and provide new clinical ideas for immunosuppressive therapy.

Data Availability

The study data presented may be made available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors report no conflicts of interest.

Authors’ Contributions

Ting Ma (email: [email protected]) and Yu-e Miao (email: [email protected]) contributed equally as the co-first authors. Guo-qing Zhang (email: [email protected]) and Jin Chang (email: [email protected]) contributed equally as the corresponding author.

Acknowledgments

This study was supported by Shandong Province Medical and Health Science and Technology Development Plan (Grant no.: 2019WS400).

References

Z. C. Liu, Z. X. Li, and Y. Zhang, “Interpretation of 2020 global cancer statistical report,” Journal of Multidisciplinary Cancer Management, vol. 7, no. 2, pp. 1–14, 2021.
View at: Google Scholar
A. K. Ganti, A. B. Klein, I. Cotarla, B. Seal, and E. Chou, “Update of incidence, prevalence, survival, and initial treatment in patients with non–small cell lung cancer in the US,” JAMA Oncology, vol. 7, no. 12, pp. 1824–1832, 2021.
View at: Publisher Site | Google Scholar
W. D. Travis, E. Brambilla, and G. J. Riely, “New pathologic classification of lung cancer: relevance for clinical practice and clinical trials,” Journal of Clinical Oncology, vol. 31, no. 8, pp. 992–1001, 2013.
View at: Publisher Site | Google Scholar
C. Allemani, T. Matsuda, V. Di Carlo et al., “Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries,” The Lancet, vol. 391, no. 10125, pp. 1023–1075, 2018.
View at: Publisher Site | Google Scholar
R. L. Siegel, K. D. Miller, H. E. Fuchs, and A. Jemal, “Cancer statistics, 2022,” CA: a Cancer Journal for Clinicians, vol. 72, no. 1, pp. 7–33, 2022.
View at: Publisher Site | Google Scholar
H. Zhang, D. H. Fagan, X. Zeng, K. T. Freeman, D. Sachdev, and D. Yee, “Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation,” Oncogene, vol. 29, no. 17, pp. 2517–2527, 2010.
View at: Publisher Site | Google Scholar
J. S. Kim, E. S. Kim, D. Liu et al., “Prognostic impact of insulin receptor expression on survival of patients with nonsmall cell lung cancer,” Cancer, vol. 118, no. 9, pp. 2454–2465, 2012.
View at: Publisher Site | Google Scholar
J. H. Law, G. Habibi, K. Hu et al., “Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival,” Cancer Research, vol. 68, no. 24, pp. 10238–10246, 2008.
View at: Publisher Site | Google Scholar
M. Saisana, S. M. Griffin, and F. E. B. May, “Insulin and the insulin receptor collaborate to promote human gastric cancer,” Gastric Cancer, vol. 25, no. 1, pp. 107–123, 2022.
View at: Publisher Site | Google Scholar
L. Li, Y. Liang, L. Kang et al., “Transcriptional regulation of the Warburg effect in cancer by SIX1,” Cancer Cell, vol. 33, no. 3, pp. 368–385.e7, 2018.
View at: Publisher Site | Google Scholar
S. Tanaka, T. Ito, and J. R. Wands, “Neoplastic transformation induced by insulin receptor substrate-1 overexpression requires an interaction with both Grb2 and Syp signaling molecules,” Journal of Biological Chemistry, vol. 271, no. 24, pp. 14610–14616, 1996.
View at: Publisher Site | Google Scholar
L. Ai, A. Xu, and J. Xu, “Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond,” Regulation of Cancer Immune Checkpoints, vol. 1248, pp. 33–59, 2020.
View at: Publisher Site | Google Scholar
K. C. Ohaegbulam, A. Assal, E. Lazar-Molnar, Y. Yao, and X. Zang, “Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway,” Trends in Molecular Medicine, vol. 21, no. 1, pp. 24–33, 2015.
View at: Publisher Site | Google Scholar
J. Qu, Q. Mei, L. Liu et al., “The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer,” Therapeutic Advances in Medical Oncology, vol. 13, p. 175883592199296, 2021.
View at: Publisher Site | Google Scholar
P. N. Aguiar Jr., R. A. De Mello, P. Hall, H. Tadokoro, and G. D. Lima Lopes, “PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data,” Immunotherapy, vol. 9, no. 6, pp. 499–506, 2017.
View at: Publisher Site | Google Scholar
C. Wang, T. Lu, R. Xu et al., “A bioinformatics-based immune-related prognostic index for lung adenocarcinoma that predicts patient response to immunotherapy and common treatments,” Journal of Thoracic Disease., vol. 14, no. 6, pp. 2131–2146, 2022.
View at: Publisher Site | Google Scholar
A. J. Piper, J. L. Clark, J. Mercado-Matos et al., “Insulin receptor substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC),” PLoS One, vol. 14, no. 8, article e0220567, 2019.
View at: Publisher Site | Google Scholar
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
View at: Publisher Site | Google Scholar
R. J. DeBerardinis and N. S. Chandel, “Fundamentals of cancer metabolism,” Science Advances, vol. 2, no. 5, article e1600200, 2016.
View at: Publisher Site | Google Scholar
P. Vaupel, H. Schmidberger, and A. Mayer, “The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression,” International Journal of Radiation Biology, vol. 95, no. 7, pp. 912–919, 2019.
View at: Publisher Site | Google Scholar
Y. Zhou, F. Tozzi, J. Chen et al., “Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells,” Cancer Research, vol. 72, no. 1, pp. 304–314, 2012.
View at: Publisher Site | Google Scholar
T. Oronsky, N. Oronsky, G. Fanger et al., “Follow the ATP: tumor energy production: a perspective,” Anti-Cancer Agents in Medicinal Chemistry, vol. 14, no. 9, pp. 1187–1198, 2014.
View at: Publisher Site | Google Scholar
Y. Zhao, E. B. Butler, and M. Tan, “Targeting cellular metabolism to improve cancer therapeutics,” Cell Death & Disease, vol. 4, no. 3, pp. e532–e532, 2013.
View at: Publisher Site | Google Scholar
C. C. Barron, P. J. Bilan, T. Tsakiridis, and E. Tsiani, “Facilitative glucose transporters: implications for cancer detection, prognosis and treatment,” Metabolism, vol. 65, no. 2, pp. 124–139, 2016.
View at: Publisher Site | Google Scholar
J. Y. Sung, G. Y. Kim, S. J. Lim, Y. K. Park, and Y. W. Kim, “Expression of the GLUT1 glucose transporter and p53 in carcinomas of the pancreatobiliary tract,” Pathology-Research and Practice, vol. 206, no. 1, pp. 24–29, 2010.
View at: Publisher Site | Google Scholar
C. Yin, B. Gao, J. Yang, and J. Wu, “Glucose transporter-1 (GLUT-1) expression is associated with tumor size and poor prognosis in locally advanced gastric cancer,” Medical Science Monitor Basic Research, vol. 26, article e920778, 2020.
View at: Publisher Site | Google Scholar
D. Kraus, J. Reckenbeil, N. Veit et al., “Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation,” Cellular Oncology, vol. 41, no. 5, pp. 485–494, 2018.
View at: Publisher Site | Google Scholar
E. B. Butler, Y. Zhao, C. Muñoz-Pinedo, J. Lu, and M. Tan, “Stalling the engine of resistance: targeting cancer metabolism to overcome therapeutic resistance,” Cancer Research, vol. 73, no. 9, pp. 2709–2717, 2013.
View at: Publisher Site | Google Scholar
R. Courtnay, D. C. Ngo, N. Malik, K. Ververis, S. M. Tortorella, and T. C. Karagiannis, “Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K,” Molecular Biology Reports, vol. 42, no. 4, pp. 841–851, 2015.
View at: Publisher Site | Google Scholar
A. Barthel, S. T. Okino, J. Liao et al., “Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1,” Journal of Biological Chemistry, vol. 274, no. 29, pp. 20281–20286, 1999.
View at: Publisher Site | Google Scholar
H. M. Wang, Y. J. Lu, L. He et al., “HPV16 E6/E7 promote the translocation and glucose uptake of GLUT1 by PI3K/AKT pathwayviarelieving miR-451 inhibitory effect on CAB39 in lung cancer cells,” Therapeutic Advances in Chronic Disease, vol. 11, p. 204062232095714, 2020.
View at: Publisher Site | Google Scholar
J. Yu, J. Li, S. Zhang et al., “IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells,” Brain Research, vol. 1430, pp. 18–24, 2012.
View at: Publisher Site | Google Scholar
J. Jiang, H. Y. Ren, G. J. Geng et al., “Oncogenic activity of insulin in the development of non-small cell lung carcinoma,” Oncology Letters, vol. 15, no. 1, pp. 447–452, 2018.
View at: Publisher Site | Google Scholar
S. M. Heckl, F. Mau, A. Senftleben et al., “Programmed death-ligand 1 (PD-L1) expression is induced by insulin in pancreatic ductal adenocarcinoma cells pointing to its role in immune checkpoint control,” Medical Science, vol. 9, no. 3, 2021.
View at: Google Scholar
X. Liu, K. Yamaguchi, K. Takane et al., “Cancer-associated IDH mutations induce Glut1 expression and glucose metabolic disorders through a PI3K/Akt/mTORC1-Hif1α axis,” PLoS One, vol. 16, no. 9, article e0257090, 2021.
View at: Publisher Site | Google Scholar
J. Chen, C. C. Jiang, L. Jin, and X. D. Zhang, “Regulation of PD-L1: a novel role of pro-survival signalling in cancer,” Annals of Oncology, vol. 27, no. 3, pp. 409–416, 2016.
View at: Publisher Site | Google Scholar
R. Zhao, Y. Song, Y. Wang et al., “PD-1/PD-L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway,” Cell Proliferation, vol. 52, no. 3, article e12571, 2019.
View at: Publisher Site | Google Scholar
T. S. Stutvoet, A. Kol, E. G. E. de Vries et al., “MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells,” The Journal of Pathology, vol. 249, no. 1, pp. 52–64, 2019.
View at: Publisher Site | Google Scholar
L. M. Shaw, “The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer,” Cell Cycle, vol. 10, no. 11, pp. 1750–1756, 2011.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Ma Ting et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

294

Downloads

438

Citations