Review
Sofoklis Stavros 1,2, Kalliopi Pappa1, Peter Drakakis 1,2
11stOB.GYN Department, School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, Vasilissis Sofias Ave, 11528 Athens, Greece, 2Molecular Biology of Reproduction Unit and Recurrent Abortions Unit, Assisted Reproduction Division, 1st Ob/Gyn Dept, Medical School, National and Kapodistrian University of Athens, Greece
Correspondence: Sofoklis Stavros, MD PhD, Obstetrician and Gynecologist, Fellow of the 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, General Hospital of Athens ‘ALEXANDRA’, Vasilissis Sofias Ave, 11528 Athens, Greece +306906725017 (mobile) / e-mail: sfstavrou@yahoo.com
Abstract
The PI3K/PDK1/Akt pathway can regulate a large variety of cellular processes such as cell growth, proliferation and survival. Moreover, it is one of the most frequently altered networks in cancer though. The dysregulation of these pathways has been reported in several human cancers, as well as in diabetes, neurological diseases and cardiovascular diseases. Cervical carcinogenesis seems to be associated with increased levels of activated AKT kinase. Moreover, PTEN inactivation is the most common genetic alteration in type1 endometrial cancer. In addition, the PI3K /AKT pathway is related to ovarian carcinomas cell motility and adhesion. This pathway plays an imperative role in cell survival and except for that, it may lead to metastatic and invasive phenotypes of a large variety of malignant cells. A battery of cancerous types has been associated with PI3K/AKT hyperactivation; inhibition of this pathway has been described as a treatment option of malignancy. The role of PI3K-PDK-AKT signaling pathway in gynecological malignancy seems to play a pivotal role, but it necessitates further investigation, which could lead to novel therapeutic strategies of eventual robust advantages to many cancer patients. The aim of that review is to highlight and underline the role of those pathways paving the way of gynecological malignancy.
Introduction
The PI3K/PDK1/Akt pathway can regulate a large variety of cellular processes such as cell growth, proliferation and survival1. Moreover, it is one of the most frequently altered networks in cancer2. The dysregulation of these pathways has been reported in several human cancers, as well as in diabetes, neurological diseases and cardiovascular diseases. The different components which take part in this pathway consist important and attractive targets for the therapy1.
Discussion
Mirza et al, in a recent study suggests that PI3K/PDK/AKT and RAF/MEK/ERK pathways may collaborate to advocate G0-G1-S phase cell cycle progression in normal and cancer cells alike; this cooperation between them can promote the multiplication of normal cells as well as the abnormal proliferation of cancer cells3.
Activation of the Akt/PI3K pathway can be occurred via binding of ligands, i.e. cytocines, growth factors or insulin, to cell membrane receptor tyrosine kinases, leading to autophosphorylation of their intracellular domain. This allows for conformational changes and subsequent phosphatidylinositol 3-kinase (PI3K) activation, a heterodimeric protein consisting of a catalytic (p110) and regulatory (p85) subunit. Based on the differences in structure, PI3K has been divided into three classes (I, II and III); among them, class I plays a crucial role in the onset of many cancers, the most thoroughly researched. PI3K leads to transformation of phosphatidylinositol 4, 5-bisphosphate (PIP2) to phosphatidylinositol 3, 4, 5-trisphosphate (PIP3), which in turn, via phosphoinositide-dependent kinase 1 (PDK1), allows for phosphorylation and activation of the Akt protein. PTEN and INPP4B exert a contradictory effect in cells, transforming PIP3 to PIP2 and PIP2 to PIP1, respectively4.
The family of phosphatidylinositol 3- kinase was first described in the mid-1980s and until now, it plays a pivotal role in cellular functions such as multiplication and survival5. PI3k proteins are heterodimers containing two subunits in their form; the catalytic p110 subunit and the regulatory p85 subunit6. Three isoforms of p110 have been described: pd110α, p110 β and p110 δ consisting all products of separate genes (PIK3CA, PIK3CB and PIK3CD, respectively)5. Regarding subunits p85, five categories have been revealed, including p85α, p85β, p55α, p55γand p50 α7. Based on their lipid substratum, function and structure PI3K proteins divided into three categories; class I, II and class III5. Class IA enzymes are activated mostly by tyrosine kinase receptors and special oncogenes such as RAS (rat sarcoma), while Class IB is exclusively activated by G protein – coupled receptors5.
The class IA PI3-K signaling cataract plays a major role, connecting multiple receptors to many processes such as cell cycle, cell survival protein synthesis, metabolism, growth and angiogenesis through other protein families including SGK and AKT7.
Recruitment of PDK1 and AKT plays an important role in interaction of the two kinases. PDK can phosphorylate and fully activate AKT at threonine 308 after the phosphorylation of AKT at the serine 473 site by MTORC2 (mammalian target of rapamycin complex 2)5,7.
Desregulations of the components of PI3K pathway, such as PI3K, PTEN (phosphatase and tensin homolog) and AKT, seem to play a pivotal role in human cancer and especially occur in PIK3CA gene and tumor suppressor PTEN7.
In addition, abnormal mutations in PI3K pathway can also be presented in cancers after receptor tyrosine kinases mutation5.
Mutations in AKT family genes have also been presented in human cancers; a single amino acid substitution, E17K, in the plecstrin homology domain may also lead to constitutive recruitment of AKT to the membrane5.
AKT2 was amplified and over expressed in a subset of ovarian malignancies; more specifically two out of eight ovarian tumor cell lines and two of 15 primary ovarian malignancies have been reported based on the above alterations8. In addition, AKT2 has been described that can be amplified in non-Hodgkin lymphomas9. Furthermore, amplification and /or overexpression of AKT2 has been presented in 10-20% of primary pancreatic malignancies and cell lines of pancreatic tumours10,11,12. Moreover almost 40% of hepatocellular carcinomas are related to an increased expression of AKT2, where the overexpression of AKT2 plays an independent prognostic role13.
Instead AKT2, AKT1 is amplified not so frequently based on bibliography. Staal and al have shown that AKT1 amplification is associated with gastric carcinomas14, while in a more recent investigation of 103 glial tumors, AKT1 amplification and overexpression were revealed in a single case of gliosarcoma15.
AKT3 high level amplification has not been reported in human malignancies. Small increases in a number of AKT3 copies are expected in a subset of tumors. Estrogen receptor –negative breast tumors have been shown an upregulation of AKT3 m RNA16.
Advanced disease and poor prognosis are related to AKT activation in some types of malignancy. Recent study has shown that approximately 40% of ovarian and breast malignancies and more than the half of prostate malignant lesions exhibit increased AKT1 kinase activity; the most imperative result of this study is that almost the 80% of these malignancies were stage III/IV cancers and grade 3 as well 17. Other studies have revealed that activation of AKT2 kinase was reported in 30 to 40% of ovarian and pancreatic malignant lesions18,19.
The PIP3 as a PI3K product is an anchor for the further recruitment of downstream effectors such as PDK1 and AKT. PIP3 is a crucial component of PI3K-mediated oncogenesis. The activation of PI3K or inactivation of PTEN (phosphatase and tensin homolog) can trigger increased levels of PIP3.This last finding is frequently revealed in tumor cells1.
Pathways and Cervical carcinoma
Cervical carcinoma is the second most common malignancy of female reproductive tract and ranks second among female deaths caused by cancers20. In a recent research, Bertelsen et al, showed that cervical carcinogenesis seems to be associated with increased levels of activated AKT kinase; this can be explained by PIK3CA amplification, whereas PTEN mutation may not play such an important role21.
Furthermore, PTEN’s loss of function may lead to activation of this pathway via PIP3 accumulation. Inactivating mutations of the tumor suppressor gene, PTEN, have been detected in endometrial and ovarian cancer alike. PTEN is an inhibitor of PI3K/ AKT signaling as well as it controls the rate of cell division and promote apoptosis. Thus, the fundamental in vivo role of PTEN is to inhibit the PI3K–AKT pathway. Mutation of PTEN can disable this inhibitory function, thus inducing the antiapoptotic pathway, which is believed to be the key to endometrial carcinogenesis22.
Pathways and Endometrial carcinoma
PTEN inactivation is the most common genetic alteration in type1 endometrial cancer. The highest rates (83%) occur in sporadic cases with a simultanusly or a prior premalignant lesion. Moreover, the pivotal role of PTEN in endometrial cancer type 1 has been reported in PTEN knockout mice with a percentage of 20 % endometrial cancer development. Opposite to type 1 endometrial malignancy, loss of PTEN isn’t reported in type 2 endometrial tumors. Type I endometrial carcinogenesis has been related with a variety of hormonal mechanisms such as the influence of estrogens; earlier endometrial stages, precancer lesions and endometrial intraepithelial neoplasia (EIN) have been shown to maintain high levels of nuclear estrogen and progesterone receptors and under conditions of estrogen stimulation it is hypothesized that PTEN defective cells would have a selective proliferative advantage since PTEN would not carry out its normal role to limit the rate of cell division23.
Pathways and Ovarian carcinoma
Among women in Europe and United States, ovarian carcinoma consists the fourth pivotal causal factor of cancer mortality. Its early diagnosis is difficult because lacks specific clinical symptoms of this entity. On the other hand, its late detection leads to poor survival rates for the diagnosed patients. Numerous causal factors have been associated with ovarian carcinomas development such as the age, the hormonal profile (early or late menopausal women, infertility, endometriosis), genetic factors and environmental factors (smoking, diet, obesity)24.
The PI3K /AKT pathway is related to ovarian carcinomas cell motility and adhesion. This pathway plays an important role in cell survival and except for that, it may lead to metastatic and invasive phenotypes of a large variety of malignant cells. A battery of cancerous types has been associated with PI3K/AKT hyperactivation; so, inhibition of this pathway can be considered as a treatment option of malignancy24.
Overexpression and/or activation of the PI3K/Akt survival pathway have been revealed to carcinogenesis of numerous tissue types. In a recent study, Wu et al showed that the phosphorylated AKT levels are increased in chemo resistant ovarian malignancy. Hence, therapy including Akt inhibitor leads to increased sensitivity to anticancer drugs. In addition, this study further showed that COL11A1 (collagen type XI alpha 1) may lead to increased phosphorylated Akt in chemo resistant ovarian cancer cells via stabilizing PDK1 protein. Moreover, Wu et al, revealed that phosphorylated Akt levels in chemo resistant ovarian carcinomas are increased by COL11A1 due to enhanced binding activity between PDK1 and COL11A1. Over the course of this study, an important result has been revealed; the overexpression of COL11A1 leads to chemoresistance, possibly by binding to PDK1-akt, and subsequently preventing PDK1 degradation. This binding may prevent cisplatin- and paclitaxel-induced PDK1 ubiquitination and degradation in these cells24.
Conclusion
Since its in initial discovery as a proto-oncogene, the serine /threonine kinase Akt (also known as PKB) has become a major focus of attention because of its pivotal and critical role in regulating diverse cellular functions as well as is one of the most common pathways leading to human malignancy. The role of PI3K-PDK-AKT signaling pathway in gynecological malignancy seems to play a pivotal role, but it necessitates further investigation, which could lead to novel therapeutic strategies of eventual advantages to many cancer patients.
References
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Received 29-7-2019
Revised 3-9-2019
Accepted 16-9-2019