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. Author manuscript; available in PMC: 2016 Dec 15.
Published in final edited form as: Glob J Biochem. 2011 Mar 8;3:3.

The Phosphatidylinositol 3-kinase/Akt Signaling Pathway in Neuroendocrine Tumors

Yash R Somnay 1, Muthusamy Kunnimalaiyaan 1,*
PMCID: PMC5157925  NIHMSID: NIHMS826731  PMID: 27990410

Abstract

The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is often aberrantly activated in neuroendocrine-derived cancers. Therefore, selectively targeting this pathway using small-molecule inhibitors may reduce neuroendocrine tumor burden, potentiate adjunct therapies, and achieve symptomatic control for patients with hormonally active and inoperable disease. Here, we discuss the role of the PI3K-Akt pathway in the malignant transformation of neuroendocrine tumors, specifically carcinoids and small cell lung cancers. The collective findings presented in this review propose that selective targeting of the PI3K-Akt pathway may mitigate neuroendocrine tumor progression, thus offering a viable therapeutic approach for managing systemic disease.

Keywords: Raf-1 pathway, Notch pathway, Akt, NE Tumors, Carcinoids, SCLC, ASCL1, Chromogranin A

1. Introduction

Several signal transduction pathways have been identified as key regulators of neuroendocrine (NE) tumor (NET) viability, some of which include the Raf-1/MEK/ extracellular signal-regulated kinase (ERK) pathway, the Notch-1/hairy enhancer of split 1 (HES-1)/Achaete-scute complex-like 1 (ASCL1) pathway, and the phosphatidylinositol 3’ kinase (PI3K/Akt) pathway [1–9]. Collectively, these form an intricately woven network of signaling cascades that regulate the growth, differentiation, and phenotypic expression among NE neoplasms, therein offering potential therapeutic targets for controlling tumor progression [1–9]. Over the past 20 years, the PI3K-Akt signaling pathway has been regarded as a key phenotypic determinant in NETs, along with breast cancer, prostate, colon and ovarian cancers [10].

In normal cell physiology, the PI3K-Akt pathway regulates such functions as mitogenesis, motility, and protection from apoptosis [11, 12]. Class I of PI3K is a heterodimeric enzyme comprised of two subunits: a p85 regulatory subunit and a p110 catalytic subunit, both of which are indispensible to kinase activity. The p85 subunit consists of two SH2 domains that can interact with phosphotyrosine. PI3K is translocated to the inner face of the plasma membrane and recruited close to its lipid substrates. Active class I PI3K then acts by phosphorylating phosphatidylinositol-4,5-bisphosphate (PIP2) which generates phosphatidylinositol-3,4,5-triphosphate (PIP3). Next, PIP3 recruits Akt/protein kinase B, a serine threonine kinase, and inositol phosphate-dependent dehydrogenase kinase-1 (PDK-1). Finally, Akt is phosphorylated, either directly by PIP3 or through PDK1. Activation of Akt enables it to phosphorylate and interact with an array of downstream effectors that regulate apoptosis, cell-cycle arrest, and viability. Among these downstream substrates include various caspases, the Bcl-2-associated death promoter (BAD), mammalian target of rapamycin (mTOR), and Activator protein 1 (AP-1), in addition to transcription factors such as Nuclear Factor-kappa B (NFκB) and Forkhead transcription factor (FKHR1) [13–15].

The oncogenic potential of a dysregulated PI3K-Akt pathway is no exception in the case of NETs. In developing malignancies, normal pro-survival mechanisms controlled by the PI3K-Akt pathway are hijacked as a result of mutations, thereby genetically selecting for cells that have undergone malignant transformation. Aberrant activation of the proto-oncogene Akt thus initiates, and further potentiates the progression of a variety of cancers, including carcinoids, medullary thyroid, and small cell lung cancers [4, 16]. Here forth, we shall discuss the role of the PI3K-Akt pathway in the pathogenesis of carcinoids and small cell lung cancers (SCLC).

2. Carcinoid

Carcinoid tumors are slow-growing neuroendocrine (NE) malignancies that comprise nearly 50% of all NETs. Carcinoids have a reported incidence of approximately 2–3:100,000, with nearly 5,000 annually diagnosed cases in the United States, according to the American Cancer Society [17, 18]. These tumors arise from the enterochromaffin cells of the gastrointestinal or bronchopulmonary system. Because carcinoids follow an indolent course, their diagnosis is often delayed and incidental. Consequently, most carcinoids are not diagnosed until clinically apparent metastasis, or symptomatic manifestation of the carcinoid syndrome. In fact, carcinoids stand as the 2nd most common cause of isolated hepatic metastasis after colorectal cancer [19]. Therefore, while surgery remains the only curative option, carcinoid patients more frequently present with unresectable conditions [19].

The carcinoid syndrome results from the hypersecretion of an array of bioamines, hormones and neuropeptides, that lead to a constellation of debilitating symptoms including flushing, diarrhea, skin rashes, and heart failure. To date, systemic therapies for carcinoids have shown limited antitumor efficacy [20]. Current mainstay therapies for carcinoids, therefore, focus mainly on symptomatic management. Somatostatin analogs like Octreotide, tend to be more effective at ameliorating symptoms of the carcinoid syndrome than at inhibiting tumor growth [21–24,26]. Systemic chemotherapy, ablative procedures or hepatic artery embolization may also be employed to alleviate carcinoid syndrome symptomatology and prolong the life of the carcinoid patient.

Our group has implicated several signaling pathway derangements in the growth, differentiation, and bioactivity of NETs. Among these, the PI3K-Akt pathway is known to be basally hyperactive in the setting of NE oncogenesis [13, 26]. Understanding the intricacies of the PI3K-Akt pathway in the pathogenesis of carcinoids may help to identify potential molecular targets for novel and more effective therapies against these malignancies.

Recently, we have elucidated the role of the PI3K-Akt pathway in human gastrointestinal (GI) carcinoids. PI3K-Akt signaling was effectively inhibited using either the PI3K inhibitor LY294002, which binds to the p110 subunit of the enzyme thereby preventing its ability to phosphorylate Akt, or following siRNA transfection against the Akt1 isoform [13]. Both treatments markedly decreased BON cell growth, while suppressing expression of NE markers ASCL1 and chromogranin A (CgA). This antitumor mechanism occurred through the induction of cell-cycle arrest, as was evidenced by the increased expression of p27Kip1 alongside decreased cyclin D1 [13]. Furthermore, knockout of Akt1 suppressed carcinoid cell growth along with NE hormone production in an isoform-specific manner. This suggests that Akt1 along with other Akt isoforms may play a role in GI carcinoid progression [13].

Additional investigations have further delineated the role of the PI3K-Akt pathway and its associated effectors in GI carcinoids. Akt activation can be potentially inhibited by the Phosphatase and Tensin homolog (PTEN), which is located on the chromosomal band 10q23. PTEN is a well-established tumor suppressor, which acts by preventing PIP2 and PIP3 phosphorylation through PI3K inhibition. Thus, mutations that deter the activity of PTEN consequently result in elevated levels of activated Akt [10]. In fact, a loss of PTEN is a common hallmark of a number of cancers, as it results in constitutive PI3K-Akt pathway activation and tumorigenesis [26–29]. In order to investigate the role of PTEN and Akt in GI carcinoids, an expression profile of these biomarkers were obtained from a panel of human GI carcinoid tissue samples. Among the specimens that were examined, all exhibited ample expression of PTEN, phosphorylated Akt (pAkt) and total Akt [30]. Additionally, the pAkt:PTEN ratio correlated positively and significantly with patients’ serum levels of CgA, reflecting that pAkt may contribute to carcinoid bioactivity. It was also demonstrated that patients with pAkt:PTEN ratios greater than 1 trended toward shorter overall survival relative to those with both lower pAkt and higher PTEN levels [30]. Furthermore, these data suggest that increased Akt alongside decreased PTEN may be associated with older age among carcinoid patients. Because age is a poor prognostic factor for carcinoid patients, Akt and PTEN expression profiles may explain the age-associated decline in survival among this disease group [30–32]. In sum, these findings reflect that expression profiling of pAkt and PTEN may be a valuable prognostic parameter for carcinoid patients.

Beyond its central role in the PI3K-Akt pathway, Akt has also been explored in the context of aligned signaling pathways implicated in carcinoid tumorigenesis. Von Wichert et al. characterized the influence of factors upstream of Akt such as Insulin-like Growth Factor 1 (IGF-1), on the activity of Akt’s downstream target cyclin D1, and in doing so, defined this interplay via a PI3K-Akt pathway-mediated mechanism. Signaling pathways that influence carcinoid progression are often governed by autocrine loops such as IGF-1, which may serve as molecular triggers for both the PI3K-Akt and extracellular signal-regulated kinase (ERK) cascades [33]. Cyclin D1 is a regulatory subunit that phosphorylates and inactivates the retinoblastoma protein (Rb), a known tumor suppressor [34]. Consequently, many cancers’ malignant phenotypes, including carcinoids, may hinge on aberrantly elevated cyclin D1 expression [35–37]. We and others have reported that inactivation of the PI3K-Akt pathway in BON cells significantly reduces Akt phosphorylation alongside cyclin D1 expression, while increasing p27Kip1 [37].

Von Wichert et al. demonstrated that IGF-1 binding to the IGF receptor results in Akt phosphorylation and subsequent activation, while an immunoneutralizing antibody directed against this receptor unambiguously diminishes pAkt. These studies indicate that IGF upregulation in BON carcinoid cells acts through the PI3K-Akt pathway to induce cyclin D1. Further investigations revealed that the basal promoter activity of cyclin D1 in BON cells appears to diminish in response to treatment with the Akt inhibitor LY294002, as well as following transfection with a dominant-negative p110 (p110Δk) or Akt (dnAKT) plasmid. It has also been reported that the PI3K-Akt axis regulates transcription factors such as NFκB and AP-1.

In addition to the interconnectedness between IGF-1 and the PI3K-Akt pathway, the VEGFR-2 pathway is also influenced by functional PI3K-Akt signaling. Interestingly, studies by Silva et al. reported that inhibiting PI3K or Akt in BON cells results in an increase in VEGFR-2 mRNA and protein expression. Conversely, BON cells stably transfected with a small-hairpin RNA (shRNA) construct against PTEN exhibited elevated PI3K-Akt activity and consequently, markedly decreased levels of VEGFR-2 [39]. The inverse relationship between VEGFR-2 and PI3K-Akt activity was confirmed following experiments on athymic mice implanted with BON cell xenografts stably transfected with PTEN-shRNA, thus resulting in depressed VEGFR-2 [39]. These findings indicate that although VEGFR-2 is an epithelial component of carcinoid tumors, its activity is inversely regulated by the PI3K-Akt pathway. This paradoxical finding implies that VEGFR-2 exerts an inhibitory effect on BON cell proliferation, migration, and invasion [39]. The aforementioned in vivo studies found that liver metastases from the PTEN-suppressed BON cell xenografts exhibited reduced VEGFR-2 expression, corroborating that VEGFR-2 induces an antimetastatic effect in BON cells.

3. SCLC

Lung cancer stands as the most predominant cause of cancer-related deaths in the world, accounting for greater mortality than prostate, breast, and colorectal cancers combined. Of the 222,520 estimated new cases of lung cancer in the United States in 2010, 157,300 are expected to die [40]. Small cell lung cancer (SCLC) comprises approximately 15–20% of all lung cancer cases in the United States, and presents the poorest prognosis [41].

A plethora of research suggests that the PI3K-Akt-mTOR pathway plays a crucial role in enabling the aggressive phenotype of SCLC [14, 42]. In fact, one of the first reports on PI3K-Akt signaling in SCLC found the pathway to be both constitutively activated, and central to mediating anchorage-independent proliferation. Signaling through the PI3K-Akt pathway culminates in Akt phosphorylation at the serine 473 and/or threonine 308 positions [43]. Subsequently, Akt activates a series of pro-survival mechanisms, conferring SCLC’s their tumorigenic state.

The etiopathogenesis of SCLC has been highly attributed to tobacco use, with about 98% of cases being smoking-related [44]. This correlation may suggest a nicotine-mediated mechanism of Akt activation in SCLC. Of note, recent public trends in reduced tobacco use, as well as improvements in the safety and composition of cigarettes have appeared to occur alongside a marked decrease in SCLC incidence, falling from 25% in 1993 to 12.5% in 2002 [45]. Studies on the effects of nicotine along with the tobacco-specific carcinogen 4- (methyulnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on lung cancer cell survival have established its role as an activator of the Akt pathway, along with its downstream targets GSK3, FKHR, mTOR, 4E-BP1 and S6K1 [46]. Nicotine-induced Akt activation was shown to cause increased phosphorylation of the BAX protein, a known regulator of apoptosis, and inhibition of the anti-apoptotic marker BAD, thus conferring cells a more robust defense against apoptotic or antitumor stimuli [47, 48]. While this proposed nicotinic response remains hypothetical for SCLC tumors, it may suggest a valid platform by which Akt contributes to SCLC survival following exposure to tobacco smoke [45].

Comparative analyses of genomic differences among SCLCs has identified several genes as exhibiting copy-number variations, some of which encode known drug targets [44]. Recent studies by Voortman et al. employing the method of array comparative genomic hybridization (aCGH) to explore genomic alterations in SCLCs revealed high-frequency copy alterations in genes involved in the PI3K-Akt cascade [44]. Genes with high-frequency copy-number gains included AKT1, PIK3CA, and FRAP1, which encode the proteins Akt, PI3K, and its downstream target, mammalian target of Rapamycin (mTOR), respectively [44]. Among the copy number losses included the PTEN gene, a known inhibitor of the PI3K-Akt-mTOR pathway [44]. Other notable drug targets exhibiting copy-number variations included p21, p53, BRCA1/2, c-Kit, Src, and EGFR [44]. The ability to delineate gene-specific alterations in SCLC lines using comparative genomics may help forge new and effective approaches to multi-targeted drug therapy.

Investigations into the mechanisms underlying Akt activation have suggested that various PI3K isoforms of classes I and II are overexpressed in SCLC cell lines [49]. It has also been established that induction of specific PI3K isoforms necessary for functional Akt signaling are mediated downstream of particular RTKs. In SCLC cell lines, RTK stimulation by the stem cell factor (SCF), Insulin like growth factor-1 (IGF-1) or even serum, activated the PI3K-Akt pathway, consequently conferring a pro-survival, and chemoresistant state. Contrastingly, concomitant inhibition of the PI3K-Akt pathway alongside RTK stimulation blocked these effects [16]. Thus, specific RTK-receptor inhibitors may serve purposeful in enhancing suppression of the PI3K-Akt-mTOR pathway via upstream targeting.

In response to RTK stimulation, the activation of specific PI3K isoforms (class I and II) appears to differentially regulate Akt phosphorylation [49]. While the PI3K p110α (class Ia) and C2β (class II) isoforms are triggered downstream of certain RTKs, only the PI3K C2β is capable of inducing Akt phosphorylation [49]. Reported by Fischer et al., this was the first demonstration of an isoform-specific activation of Akt in SCLC cell lines [45]. These findings provide rationale for narrowing the target-specificity of emerging therapeutics towards specific upstream isoforms of the Akt pathway. Furthermore, the PI3K class Ia isoform was also shown to complex with Src kinases and c-Kit, ultimately potentiating SCLC cell survival via the activation of Akt [49]. Interestingly, comparative genomic analysis conducted by Voortman et al. found Src and c-Kit to be highly upregulated in SCLC [44]. Hence, the Src/c-Kit/PI3K interplay may enhance functional Akt activity, contributing to the characteristic tumorigenic phenotype of SCLC [49]. Targeting such complexes may optimize inhibition of pAkt and its associated oncogenic factors to ultimately improve prognoses for SCLC patients.

Among other downstream effectors of the Akt pathway include pro-apoptotic factors of the Bcl-2 family, in addition to pro-caspase-9. Past studies have reported that Akt phosphorylates the pro-apoptotic Bcl-XL/BAD complex, leading to its dissociation and subsequent inactivation [50]. Like many lung cancers, SCLCs have been shown to express elevated levels of Akt, in addition to phosphorylated BAD. This increase in BAD expression allows cells to exhibit an exaggerated pro-survival state and evade apoptosis. This has been demonstrated in multiple SCLC cell lines [41, 50]. In response to Akt induction, activation of its downstream target NFκB, a universal transcriptional regulator of pro-survival mechanisms, likely contributes to SCLC’s malignant phenotype [15].

Combinatorial therapies employing targets against the PI3K-Akt-mTOR axis and other tumorigenic signaling pathways have been widely pursued. While this method has not been entirely elucidated in SCLC specifically, the interdependence of the PI3KAkt-mTOR pathway on the general biomolecular framework of SCLC progression provides strong rationale for a multi-targeted approach to its treatment [14]. Initially, it was demonstrated that Akt regulates mTOR activity following phosphorylation of TSC2, a component of tuberous sclerosis complexes 1 and 2. Activation of mTOR subsequently leads to the phosphorylation and activation of 4EBP-1 and p70s6K, hence promoting cell proliferation [14]. Recent evidence also suggests that EGFR may activate the PI3K-Akt-mTOR pathway [51, 52]. As EGFR is an already established therapeutic target in the treatment of solid tumors, in addition to being overexpressed in SCLC, the functional link between EGFR and Akt implies the potential for synergy via simultaneous therapeutic targeting of these pathways [14]. Schmid et al. demonstrate that the EGFR inhibitor Erlotinib, when administered in combination with the mTOR inhibitor RAD001 (Everolimus), synergistically inhibited SCLC cell viability in vitro [14]. Furthermore, a dramatic decrease in Akt phosphorylation along with mTOR expression was observed following combinatorial treatment with other mTOR inhibitors in combination with Erlotinib, as compared to Erlotinib treatment alone [14]. Moreover, both RAD001 and Erlotinib were nearly ineffective as lone agents. This may explain the high frequency of relapse among SCLC patients treated mono-therapeutically with either EGFR or mTOR-targeted inhibitors.

Confronting the evasiveness of SCLC in response to prolonged chemo- and radiotherapy has been the focus of a multitude of scientific and clinical investigations over recent years. Interestingly, the Akt-PI3K–mTOR pathway, in addition to its role in promoting cancer progression, has been defined in SCLC as a determinant of chemoresistance via a laminin-mediated cell-survival mechanism [38,42]. Laminin-producing SCLC cell lines have been shown to increase Akt activity via β1-integrin activation. This allows SCLC cells to both resist serum-withdrawal-induced apoptosis and maintain viability in the face of other antiproliferative agents [53, 54]. However, inhibition of either PI3K or mTOR using the inhibitory agents LY294002 or Rapamycin, respectively, effectively abrogate laminin-induced chemoresistance [38,42]. Similar findings have suggested that the Akt pathway promotes resistance against gamma radiation therapy in adherent SCLC cell lines, relative to parent cell lines [41]. Furthermore, sub-cultivation of these adherent cell lines on uncoated plates reverses the Akt phenotype and restores radiosensitivity. Altogether, these findings underscore the importance of the PI3KAkt-mTOR pathway in promoting ECM-dependent SCLC survival [41].

Due to its central locality, SCLCs are typically inoperable, thus reinforcing the need for efficacious targeted therapies [40]. However, the evolution of available treatments in recent decades has only resulted in incremental improvements in the life-expectancies of SCLC patients. Given the frequency of relapse, generally after only limited periods of therapeutic response, efforts have only intensified to elucidate the molecular mechanisms that underlie SCLC chemoresistance [42]. A plethora of evidence provided here supports the clinical advent of Akt or mTOR inhibitors because of their purported capacity to enhance the efficacy of mainstay anti-cancer therapies against SCLC growth and progression. The synergistic potential between PI3K-Akt-mTOR pathway inhibitors and other agents certainly offers the possibility of improving outcomes for SCLC patients. In fact, recent trials into novel combinatorial therapeutic approaches have shown tremendous promise. These multi-drug trials have nearly doubled median survival times for SCLC patients. Integrating a multi-targeted approach into current treatment paradigms may also optimize drug-induced toxicity by permitting lower doses of a given agent, capable of achieving a commensurate therapeutic effect when part of a combinatorial regimen.

4. Conclusions

An emerging body of evidence continues to underscore the biological and therapeutic significance of the PI3K-Akt signaling pathway in NETs [4, 16]. Its function has become apparent through numerous investigations as one that is highly implicated in an intricate network of cell-signaling interactions, conferring NETs their pro-survival properties [13]. Based on the literature presented in this review, the oncogenic role of the PI3K-Akt pathway appears to be tissue-specific, thus differentially affecting any combination of processes including cell-cycle arrest, apoptosis, extracellular matrix deposition, and chemoresistance. In carcinoids, the PI3K-Akt pathway is conducive to the production of NE hormones that are responsible for the debilitating symptomatology of the carcinoid syndrome, and which may also signify the extent of metastatic spread [13, 55]. Positive correlations between pAkt and progression to the carcinoid syndrome in the setting of residual or recurrent disease have been observed, though they did not appear to be strong [30, 56]. These collective findings suggest that pharmacological targeting of the PI3K-Akt pathway would not only reduce NET tumor burden, but may effectively palliate symptoms associated with NET hormonal activity. Finally, because the PI3K-Akt pathway is involved in conferring resistance to particular chemo- and radiotherapies in NETs, concomitant inhibition of the Akt pathway alongside these agents may restore treatment efficacy at lower, less toxic doses. This approach would be especially beneficial to NET patients who have remained refractory to mono-therapeutic regimens.

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