Analysis of PI3K pathway components in human cancers
- Authors:
- Published online on: March 8, 2016 https://doi.org/10.3892/ol.2016.4309
- Pages: 2913-2918
Abstract
Introduction
Phosphoinositide 3-kinases (PI3Ks) are an evolutionarily conserved family of lipid kinases that promote various cellular functions, including cell growth, metabolism and survival (1,2). The lipid second messengers that are generated in this reaction interact with specialized lipid-binding domains that are present in a wide variety of signaling molecules. PI3Ks may be classified into one of three classes, each of which possesses different structures and characteristics (3). The PI3K pathway may be activated by upstream receptor tyrosine kinases, leading to the generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) via the phosphorylation of phosphatidylinositol-4,5-bisphosphate. The phosphatase and tensin homolog (PTEN) may dephosphorylate PIP3, which terminates PI3K signaling. The accumulation of PIP3 activates a signaling cascade, commencing with the phosphorylation (activation) of the protein serine-threonine kinase AKT (also known as protein kinase B) at threonine 308 by phosphoinositide-dependent kinase 1. Activation of AKT serves a crucial role in essential cellular functions, including cell proliferation and survival, via the phosphorylation of a variety of substrates (Fig. 1) (4).
Although the PI3K/AKT pathway has been extensively investigated in detail in distinct in vitro and in vivo systems (5), its role in molecular targeted therapy for cancer required further study. Molecular targeted therapies (e.g. inhibitors of target molecules with critical roles in tumor growth and progression) have been investigated in various cancer models, particularly hematological malignancies, such as leukemia, lymphoma and myeloma, due to the ease in obtaining samples for examination (6). The PI3K/AKT pathway has been reported to be activated in numerous types of malignancy (7), and inhibitors associated with this pathway have been shown to induce apoptosis in targeted tumor cells (8).
Aberrant activation of the PI3K pathway may promote carcinogenesis and tumor angiogenesis (9,10). For example, a previous study reported that ~30% of breast cancer cases demonstrated activating missense mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), the gene encoding the catalytic p110α subunit of class I PI3K (2); this mutated gene provides cells with a growth advantage and promotes tumorigenesis (11). In addition, dysregulated PI3K pathway signaling has been implicated in conferring resistance to conventional therapies, including biologics, hormonal therapy, tyrosine kinase inhibitors, radiation and cytotoxic drugs in breast cancer, glioblastoma and non-small cell lung cancer (12).
Wet laboratory research has revealed enormous data in the field of cancer research, and expression levels of certain proteins can be found at the Human Protein Atlas (www.proteinatlas.org). However, these proteins are not classified according to a specific disease or disorder. The aim of the present study was to utilize data deposited in the Human Protein Atlas to investigate the protein expression level of 25 proteins that are known to be implicated in the PI3K pathway in various cancer tissues. The proteins investigated were as follows: AKTIP, ARP1, BAD, GSK3A, GSK3B, MERTK-1, PIK3CA, PRR5, PSTPIP2, PTEN, FOX1, RHEB, RPS6KB1, TSC1, TP53, BCL2, CCND1, WFIKKN2, CREBBP, capase-9, PTK2, EGFR, FAS, CDKN1A and XIAP. The analysis reveals a pronounced expression of specific proteins in distinct cancer tissues, which may be potential targets for cancer treatment and provide insights into the molecular basis of cancer.
Materials and methods
Data were collected from the Human Protein Atlas database (www.proteinatlas.org) via manual searches of the desired gene names. The expression levels of 25 specific proteins that are known to be involved in the PI3K pathway were investigated in 20 different cancer tissues types: Carcinoid, glioma, liver cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, skin cancer, testis, urothelial, lung cancer, breast cancer, cervical cancer, colorectal cancer, head and neck, renal, thyroid, prostate, endometrial and stomach cancer.
The expression of the 25 proteins in the different cancer tissues were reported as high, medium or low (excluding no expression, which was considered as a separate category) relative to normal tissues as shown in the database. Thereafter, the percentage of high, medium and low expression in each tissue type was calculated by dividing the number of patients exhibiting high expression, for example, over the total number of patients in the sample for each tissue type. The number of patients per sample ranged from 8–18. Furthermore, high and medium percentages were combined as the biological impact of high and medium expression was believed to be similar. Graphs were created using Microsoft Excel 12.0 (Microsoft Corporation, Redmond, WA, USA) to represent the percentage of each level of protein expression as it was expressed in these patients.
Results and Discussion
In this study, the expression levels of 25 proteins in tissues from 20 cancer types were analyzed utilizing the Human Protein Atlas (www.proteinatlas.org). The following proteins examined: AKTIP, ARP1, BAD, GSK3A, GSK3B, MERTK-1, PIK3CA, PRR5, PSTPIP2, FOX1, RHEB, TSC1, TP53, BCL2, CCND1, WFIKKN2, CREBBP, RPS6KB1, caspase-9, EGFR, PIK2, FAS, CDKN1A, XIAP and PTEN. The physiological activity and full name of these proteins, as well as their role in cancer initiation and control, is summarized in Table I (13–43).
Table I.Summary of the physiological function and associated signaling pathways of the 25 proteins studied. |
The results revealed that 9 of the 25 proteins tested exhibited high expression levels in various cancer tissues. These proteins were PIK3CA, RPS6KB1, MERTK, RHEB, EGFR, TSC1, CCND1, TP53 and PTEN. The other 16 proteins exhibited low or no expression in tumor tissues (data not shown).
The expression level for each protein tested was categorized as either high/medium or low. The protein TSC1 exhibited high/medium expression in all types of cancer tissue tested. TSC1 exhibited ~100% high/medium expression in breast, cervical, colorectal, head and neck, lymphoma, ovarian, pancreatic, prostate, skin, stomach, testis and urothelial cancer tissues. It expression was ~90% high/medium in endometrial, glioma, liver and lung cancers (Fig. 2).
EGFR protein had high/medium expression level in >50% of carcinoid, head and neck, glioma, renal and urothelial cancer tissues (Fig. 3). For MERTK protein the high/medium expression rate was >50% in liver and thyroid cancer tissues, and 100% in renal cancer tissues. It was not detected in carcinoid, glioma, or head and neck cancer tissues (Fig. 4).
For RHEB protein, the highest expression level was present in >50% of breast, endometrial, ovarian, pancreatic and stomach cancer tissues, but was not detected in glioma and lymphoma cancer tissues (Fig. 5).
The RPS6KB1 protein expression level had ~100% high/medium in 9 cancer tissue tested: Carcinoid, colorectal, glioma, head and neck, ovarian, prostate, renal, skin and testis cancer tissues (Fig. 6).
CCND1 protein high/medium expression level was present in ~50% of head and neck cancer and melanoma tissues (Fig. 7). The high/medium expression percentage of TP53 protein was ≥50% in colorectal, head and neck, ovarian, pancreatic and urothelial tissues, but was not detected at all in carcinoid, prostate and thyroid cancer tissues (Fig. 8).
The expression level of PTEN protein (a tumor suppressor gene) was low in various cancer tissues as was expected. A high/medium PTEN expression level was present in <50% of breast, cervical, endometrial, glioma, head and neck, liver, pancreatic and skin cancer tissues; however, high/medium expression was present at a rate of ~75% in melanoma (Fig. 9).
PIK3CA protein expression level was high/medium in around 100% of lymphoma, ovarian and pancreatic cancer tissues, 90% of liver cancer tissues, 85% of melanoma and prostate cancer tissues, 70% of carcinoid and stomach cancer tissues and 65% of cervical cancer tissues (Fig. 10).
Taking this data together, the current analysis reveals a pronounced expression of specific proteins in distinct cancer tissues. These proteins may be potential candidates to serve as targets for cancer treatments and provide insights into the molecular basis of cancer. PI3Ks initiate signaling through a network of downstream effector pathways. Due to the direct implication of the pathway in numerous cancer types, this pathway has become the target for novel cancer therapies. This bird's-eye view study highlights 9 proteins that are involved in the PI3K pathway and which may be potential targets for cancer treatment. These proteins are highly expressed in several cancer tissues as indicated. Designing new drugs that modulate the activity of these proteins may decrease cancer growth, migration and metastasis.
Acknowledgements
This study was supported by Alqasemi Research Fund and the Association of Arab Universities Research Fund.
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