Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers

Abstract

Peroxisomes are indispensably involved as a central player in the metabolism of reactive oxygen species, bile acids, ether phospholipids, very-long-chain, and branched-chain fatty acids. The three subtypes of PPARs are PPAR-alpha, PPAR-delta, and PPAR-gamma which have been found to be instrumental in the control of cancer metabolism cascades. Any disproportionate expression of PPAR can lead to the progression of cell growth and survival in diverse types of cancers. It can be exploited both as an agonist or antagonist for utilization as a potential therapeutic alternative for the treatment of cancer. Therefore, the multifunctional PPAR modulators have substantial promise in various types of cancer therapies. Many recent studies led to the observations that a variety of phytochemicals, including phenolics, have been implicated in anticancer effects. Plant phenolics seem to have both palliative and treatment opportunities in combating cancer which requires deep insight into the proposed mechanisms. Henceforth, this chapter highlights the role of peroxisomal subtypes as an activator or suppressor followed by its modulation through bioactive obtained from a variety of crude drugs. A discussion on various challenges restricting proper utilization has also been incorporated.

1. Introduction

Peroxisomes are small membrane-bound organelles with simple structures but contain enzymes that display a wide range of metabolic activities. About 50 peroxisomal enzymes have been identified where major [1, 2] pathways for metabolism involve α- and β-oxidation of fatty acids, biosynthesis of ether lipids, polyamines, D-amino acids, glyoxylate, and purines. The synthesis and assembly of peroxisomal proteins occur on free ribosomes which are then imported into these tiny organelles as completed polypeptide chains. The disorders related to peroxisomal functions can be attributed to a disturbance in the formation of the organelles or might be related to defects in either a particular peroxisomal enzyme or a related transporter [3, 4]. The metabolic disorders promote the accumulation of substrates that are usually degraded by specific peroxisomal enzymes. A variety of clinical symptoms has proven to be very severe leading to an early death.

2. Metabolic implications of peroxisomes, a druggable target

Peroxisome-related homeostatic balance is an indispensable mechanism of health where the removal of worn-out and defective peroxisomes occurs through autophagy. Association with mitochondria is reflected when commotion of peroxisomal function results in disruption of mitochondrial function. The impaired peroxisomal function has been found to be instrumental in special conditions of neurodegenerative disorders and diabetes, while dysregulation in peroxisomal function can result in cancer [5, 6]. There has been increasing evidence linking peroxisomal misregulation to the eruption of several diseases which potentiate an elevated possibility of targeting peroxisomal involvement in disease prevention or treatment.

Peroxisomes are amazingly active organelles, which have an important role in lipid and hydrogen peroxide metabolism making them elemental for human health [7]. Despite great advances in identification of essential components and related molecular mechanisms, an understanding of the process by which peroxisomes are incorporated into metabolic pathways is of elementary importance. The interaction of peroxisomes with other subcellular compartments, metabolic co-operations, peroxisome–peroxisome interactions, and the interaction of peroxisomes with microtubules needs to be addressed to utilize this information directly to combat the process of disease development.

Peroxisomes are consigned to clearing up the reactive oxygen chemical debris cast off by other organelles, where their functions extend far beyond hydrogen peroxide metabolism [8]. Peroxisomes are closely associated with mitochondria, and their ability to carry out fatty acid oxidation and lipid synthesis may be highly implicated in generating cellular signals required for normal physiology. The biology of peroxisomes and their relevance to human disorders, including cancer, obesity-related diabetes, and degenerative neurologic disease cannot be undermined [9].

Peroxisomes are multifarious where they invariably modulate the metabolism of reactive oxygen species and primary homeostatic mechanisms, such as oxidation of fatty acid, synthesis of bile acid, and transport of cholesterol. Henceforth, it is implicative that peroxisomal homeostasis is an important regulator of health, and disruption of peroxisomal function can lead to mitochondrial dysfunction, reflecting the intimate link between the two organelles [10].

The impaired peroxisomal function leads to neurodegenerative disorders and diabetes, but dysregulation may have far-reaching effects, such as the development of cancer [11]. The peroxisomal function is also transformed with aging owing to deviations in the expression and/or localization of peroxisomal matrix proteins.

The homeostatic mechanisms of peroxisomes are undermined by the existence of distressing genetic disorders attributed to impaired peroxisomal function. However, with amplified evidence connecting peroxisomal dysfunction to the pathogenesis of these acquired diseases, it can be utilized as a druggable target in disease prevention or treatment [12].

The immune system evasion is one of the mainstays of cancer, and peroxisomes have an indispensable role in the regulation of cellular immune responses. Investigations of individual peroxisome proteins and metabolites provide for their pro-tumorigenic functions [13]. It is, therefore, important to highlight new advances in our understanding of biogenesis, enzymatic functions, and autophagic degradation of peroxisomes, which shall avail enough evidence to link such activities to tumor development. Such findings shall add to the possibility of exploitation of peroxisome-related processes for efficient battling against cancer.

3. Peroxisome proliferator-activated receptors (PPARs)

With the above, emerging evidence, exploring the possible sites of activation of peroxisomal receptors could be intriguing with respect to the benefit and risk ratio.

In this context, it was deduced that activation of peroxisome proliferator-activated receptors (PPARs) can be considered an efficient strategy for the treatment of metabolic dysregulation [14]. An ample of new moieties having the prospects to stimulate peroxisome proliferation have been discovered in the recent past.

The receptor which was cloned from a mouse liver, and titled a peroxisome proliferator-activated receptor (PPAR) could regulate the expression of sizable genes involved in the regulation of glucose and lipid metabolism [15].

Besides, the ligands which activate PPARs lead to the promotion of co-activators and inhibition of co-repressors remodeling the chromatin and initiating transcription [16].

4. Metabolic regulation by PPARs and their repercussions

The peroxisome proliferator-activated receptors (PPARs) are a set of nuclear receptors namely PPAR gamma, PPAR alpha, and PPAR delta, encrypted by diverse genes. PPARs are ligand-regulated transcription factors regulating gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased [17].

The PPARs are major regulators of lipid metabolism where fatty acids and eicosanoids have been recognized as common ligands. Synthetic PPAR ligands, such as fibrates and thiazolidinediones, have been effectively used in the treatment of dysregulation of lipids and glucose metabolism.

The discovery of these ligands led to the disclosure of many impending functions for the PPARs in pathological metabolic situations, such as demyelination, atherosclerosis, and cancer [18].

4.1 Peroxisome proliferator-activated receptor-alpha (PPAR-α)

It has been recognized as the nuclear receptor for a class of rodent hepato-carcinogens leading to the proliferation of peroxisomes. PPAR-α is a transcription factor that happens to be the major regulator of lipid metabolism in the liver [19].

It is primarily activated via ligand binding where fatty acids, such as arachidonic acid and their metabolites from the ligand groups. Another category consists of synthetic ligands, such fibrate drugs referred to as peroxisome proliferators [20].

4.2 Peroxisome proliferator-activated receptor beta or delta (PPAR-β or PPAR-δ)

PPAR- δ is a nuclear hormone receptor that manages diverse biological processes involved in the progression of several chronic ailments, viz. obesity, atherosclerosis, and cancer [21].

PPAR-δ act as an integrated unit for transcription regulation and nuclear receptor signaling. It stimulates the transcription of a wide variety of target genes by binding to specific DNA elements.

Many fatty acids and their derivatives induce PPAR δ viz. arachidonic acid and its metabolites [22].

4.3 Peroxisome proliferator-activated receptor gamma (PPAR-γ)

PPAR-γ or the glitazone reverse insulin resistance receptor, is a type II nuclear receptor that is encoded by the PPAR-γ gene in humans [23, 24]. The protein encoded by this gene is PPAR-γ, which regulates the differentiation of adipose cells [25]

When the activity of PPAR-γ is regulated via phosphorylation through the MEK/ERK pathway, it results in decreasing transcriptional activity of PPAR-γ. The result is a loss of insulin sensitivity due to diabetic gene modifications. Owing to the above reasons, PPAR-γ has been implicated in the pathology of numerous diseases, including obesity, diabetes, atherosclerosis, and cancer [26].

PPAR-γ controls fatty acid storage and metabolism of glucose. The genes activated by PPAR-γ stimulate lipid uptake and adipogenesis by fat cells. The agonists have been reported to be used in the treatment of hyperlipidemia and hyperglycemia [27].

PPAR-γ decreases the inflammatory response of many cardiovascular cells. PPAR-γ activates the paraoxonase-1 gene, resulting in an increase of paraoxonase 1 in the liver, which reduces the incidence of atherosclerosis [28].

The prevalence of metabolic syndromes is growing in the adult and pediatric groups which include majorly atherogenic dyslipidemia raised blood pressure, and pre-eminent plasma glucose [29].

Peroxisome proliferator-activated receptors (PPARs) may come up as potential therapeutic targets for the treatment or prevention of metabolic syndromes. Further, there is substantial evidence that its agonists are, therefore, used in the treatment of metabolic syndrome and cardiovascular diseases [30].

Activation of peroxisome proliferators-activated receptor (PPAR) is invariably indulged in varied mechanisms related to lipid profile.

One of the researches in this area confirmed the role of herbs in the stimulation of PPARα. Among the tested plant extracts, about nine had shown moderate PPARα transactivation [31]. The bioactive, piperine, and capsaicin revealed substantial trans-activational activities followed by a moderate activity in chalcones. It was concluded that a diet rich in natural products viz. herbs, act as PPARα agonists improving the lipid profile.

5. Proposed mechanisms of PPARs in tumor suppression

5.1 Distressing metabolism

PPAR ligands disturb the survival of cancer cells in such a way that the metabolism enters into complete devastation. Owing to the potential of PPAR ligands, they are been considered a potential source of anticancer agents, with minimal toxicities [32].

PPAR activation disrupts the metabolism of cancer cells mainly by blocking the synthesis of fatty acids and promoting fatty acid oxidation. Owing to nutrient depletion, in the tumor microenvironment, PPAR coordinates with AMP-dependent protein kinase in repressing oncogenic Akt activity, inhibiting cell proliferation, and inducing glycolysis-dependent cancer cells into “metabolic failure” [33].

There is substantial evidence for the antiproliferative role, and prevention of metastatic indulged by PPAR ligands, which prompts a detailed compilation on the possible potential of PPAR in tumor suppression [34].

5.2 PPAR subdues cell proliferation by overpowering inflammation

Suppression of inflammation is another mode contributing to anticancer effects. PPAR takeover the inflammation and activation of uncoupling proteins, which wanes the mitochondrial ROS generation and resultant cell proliferation. PPAR ligands can be considered as a low-toxic and well-tolerated therapeutic moiety to combat cancer [35].

The peroxisome proliferator-activated receptor γ ligands exhibited anticancer activity in vitro, against diverse neoplastic cells whereas animal studies also reflected that they are in vivo anticancer effects and chemopreventive proficiency. The effect may be attributed to slowing down the growth and induction of partial differentiation of several cancer cells, such as lipo-sarcoma, and cancers, such as colon, prostate, and breast cancers [36].

At the molecular level, these can decrease the levels of cyclin D₁ and E, nuclear factor κB, and inflammatory cytokines. Some relevant data support the fact that PPAR γ might act as a gene for tumor suppression. On the other hand, several captivating pieces of evidence, suggest that under certain specific settings, PPAR γ ligands can lead to cancer [37].

Yet, the bulk of studies still reflects the fact that PPAR γ ligands bear antiproliferative potential against numerous transformed cells and may be applied in adjuvant treatments strategies for several common tumors [37, 38, 39].

As per research by Morinishi et al., activation of PPAR-α seems to be involved in the control of colorectal carcinomas, where nuclear expression of PPAR-α may be established as an indispensable therapeutic target for the respective treatment of the disease. It was deduced that the nuclear expression of PPAR-α was significantly higher in subtly differentiated adenocarcinoma than in mucinous adenocarcinoma [40].

Colorectal cancer poses one major threat due to excessive dietary fat posing as a major threat. As it is involved in the regulation of lipid and carbohydrate metabolism, it needs to be studied extensively in this case [41]. Despite the fact, that researchers have scrutinized the expression and clinical repercussions of PPARs in colorectal cancer, the exact mechanism needs to be further explored.

Diverse studies have been undertaken, focusing on the assumed link between the polymorphisms and mutations of the PPAR γ gene with the incidence of cancer [42, 43].

Ikezoe et al. [44] analyzed 397 clinical samples and cell lines, including colon, breast, and lung cancers for mutations of the PPAR γ gene. They indicated the absence of PPAR γ gene mutations in the tested cell lines ascertaining PPAR γ mutations may occur in cancers but very rarely.

There has been substantial experimental data supporting that synthetic PPAR γ ligands induce apoptosis in several types of cancer cells [45, 46]. Albeit, the majority of the evidence has documented that PPAR γ agonists inhibit growth in cancer cells but the mechanism of the growth inhibition by PPAR γ agonists is not well understood and complicated.

5.3 Differential behavior of peroxisome

Specific tumors behave variably in terms of peroxisomal activity. It has been observed, thus, that the enzymatic activities of peroxisomal metabolism decline in the breast [47], colon [48], and hepatocellular carcinomas [49]. Similar observations were recorded in renal cell carcinoma [50]. In a related finding, von Hippel-Lindau (VHL)-deficient clear cell renal carcinoma displayed reduced peroxisomal activity. In contrast to this, some reports reveal that peroxisomal metabolic activities lead to enhancing the growth of tumors [51]. Few cancer cells count on peroxisomal lipid metabolism for energy and support the survival of cancer cells in the tumor microenvironment [52]. This controversial behavior of peroxisome indicates the fact that under a certain specific environment, it promotes or diminishes cancer growth, which may be attributed to the type of tumor. In this regard, it is implicative to further investigate the inducing factors that decide the fate of the metabolism of peroxisomes, closely related to its cancer proliferation effects.

Many studies have been undertaken to study the potential of the combinatorial approach where PPAR agonists can be used for the treatment of resistant cancers [53].

In research by Kaur et al., the probable effect of selective agonism by PPAR gamma receptors was studied for radiation therapy in non-small-cell lung carcinoma [54]. The agonist used was Rosiglitazone. A reasonably significant increase in the intensities of radiation-induced apoptosis was detected in H1299 cells attributed to enhanced PPARG expression. Consequently, it was deduced that PPAR gamma agonism stimulates the radio-sensitizing effect.

Another investigation was undertaken on the expression of PPAR gamma in human normal cervix and cervical carcinoma tissues. The effect of PPAR gamma ligands on the sustenance of cervical cancer cells was also an aim. It was observed that the PPAR gamma protein expression, was lessened in cervical carcinoma in comparison to normal cervical tissues [55].

Similar results were revealed using the effect of Ciglitizone on cell proliferation, which reflected noteworthy growth inhibition on human cervical cancer cell lines, C-33-A and C-4II. It further added to the substantial evidence for the role of PPAR in multiple human cervical cancer tissues and cell lines where a downregulation is encountered [56]. Several in vitro studies validated those high levels of free fatty acids induce the proliferation, migration, and invasion of prostate cancer cells (PC3 and 22RV1). Therefore, to test the fact, an assessment was done for serum lipid levels in patients suffering from prostate cancer in comparison to normal individuals. It was concluded that high levels of free fatty acids promote cancer by upregulation of expression in PPAR γ [57].

The fact potentiated was that obesity is undoubtedly an important risk factor, resulting in upregulation of PPAR gamma, consequently leading to incidence and progression of PCa [58]. In an interesting work, the expression of PPAR γ was studied in epithelial cells in the colon. There was a differential expression of PPAR in different segments of the colon. Specifically, in the cell lines, Caco-2, and HT-29 human adenocarcinoma cells, PPAR γ expression was amplified upon differentiation. A significant role was observed as reflected in the amplified expression of PPAR γ was observed in the colon (Table 1) [73, 74].

S. No.	Bioactive	Mechanism	References
1.	Capsaicin	Induction of apoptosis in melanoma, colon, and prostate cancer cells. It was attributed to the activation of the PPAR γ	[59]
2.	Linoleic acid	It was found to modulate interactions between PPARβ/δ and PPARγ isoforms. Conjugated linoleic acid (CLA) was able to induce apoptosis, upregulate PPARG gene expression and activate PPAR γ protein in certain human cancer cell lines.	[60, 61]
3.	β-carotene	The chemopreventive activity of β-carotene against breast cancer showed a significant increase in PPAR γ mRNA	[62]
4.	Carotenoids: Fucoxanthin	Activates PPAR-γ in cancer cells. It was reported that the edible carotenoid fucoxanthin when combined with 6-troglitazone, induced apoptosis of Caco-2 cells. oreover, in epidemiological studies, the consumption of carotenoids was shown to protect against breast cancer.	[63, 64]
5.	Kaempferol and Apigenin	It was found that flavonoids stimulated PPAR-γ transcriptional activities as allosteric effectors and are beneficial in Prostate cancer.	[65]
6.	Daidzein	They bind to the estrogen-related receptors but also PPARα and PPARγ. As a result, their biological effects are determined by the balance between activated ERs and PPARγ.	[66]
7	Triterpene glycosides: Glycyrrhizin; Triterpenoid acid: Betulinic acid	Triterpene glycoside both have shown pro-PPAR-γ activities in cancer cells.	[67]
8	Resveratrol	PPAR γ plays a role in Resveratrol-induced apoptosis of colon carcinoma cells. The combination of resveratrol with a PPARγ agonist rosiglitazone proved as an option for colorectal cancer.	[68]
9	Genistein	It impedes the OS cell cycle as a nontoxic activator of PPAR γ. It has been shown to lower the production of prostaglandin E2 in MDA-MB-231 human breast cancer cells and to reduce the invasiveness of these cells The effect of eicosapentaenoic and docosahexaenoic acids in activating PPAR γ was dependent on genistein.	[69, 70]
10	Flavone Wogonin	It has been shown that PPARα activation by wogonin downregulates osteopontin a multifunctional protein involved in several physiological and pathological events, such as cancer.	[71]
11.	Flavanones; Hesperetin, Naringenin, and their glycosides; Epigallocatechin-3-galllate	Induced expression of PPAR γ in a dose-dependent manner while naringenin was able to activate PPARα. Increases the expression of PPARα and confers susceptibility to cancer.	[72]

Table 1.

Role of bioactive in the modulation of PPARs for treatment of various cancers.

6. Challenges in anticancer strategies of peroxisomes

To exploit the peroxisomal metabolism for anticancer approaches, several constraints need to be addressed in the first place [75]. Foremost, it should be assessed for its possible side effects on non-malignant cells as overhauling the metabolism might result in serious side effects. Next, the concern might be the differential behavior of the diverse cancer cells and their lineage [76].

The tumor heterogeneity is anyhow allied with differential metabolic activities. In this context, the selection of the study group may be very crucial [77]. It may also affect the prerequisite of peroxisomal functions in a specific subset of tumors [78].

7. Discussion

PPARs, commonly known as modulators of genetic expression, exhibit variant tissue expression depending upon differential microenvironment and have thus attracted a lot of attention whether singly or in a combination strategy [25, 79].

This process can then activate the transcription of various genes involved in diverse physiological and pathophysiological processes that play main roles in the pathogenesis of several chronic diseases, such as atherosclerosis [80], diabetes [81], liver disease [82], cardiovascular diseases [83], and cancer, involving inflammatory effects and their corresponding clinical implications [84].

8. Conclusions

Though therapeutic approaches to target peroxisome metabolism in cancer have been on a rise and pursued very closely by keen researchers, not many modulators have been assessed completely. Henceforth, well-defined in vivo models have to be investigated for the potential of peroxisome inactivation to suppress cancer progression. The differential behavior of peroxisomes in different microenvironments will help to facilitate the development of a higher number of effective drugs for the modulation of peroxisomal functions [85].

Peroxisome metabolism has been invariably linked to the functions of organelles, viz. endoplasmic reticulum and mitochondria [86, 87]. The disruption of the association between the organelles and peroxisomes refurbishes the cancer cell metabolism. Further, it can be ascertained, that probable peroxisome targeting with drugs that inhibit the related organelles may lead to amplified anticancer mechanics [75].

It can be useful where targeting peroxisomes might enhance the targeting of other metabolic pathways in cancer. It, however, remains unveiled whether the alteration of peroxisome metabolism is a consequent event due to alterations in metabolism due to cellular changes during cancer or bears a prime position in the development [88].

However, it can never be disregarded that ample research has substantiated the potential of peroxisomes as absolute cancer targets while further exploration role of peroxisome metabolism in the genesis of tumors might prove to be a curtain-raiser. A rational approach to drug design can be attained by the revelation of the regulatory machinery and transcriptional focus of the PPARs. Focused research in this direction may provide a perfect perception of the development of metabolic diseases including cancer.

Acknowledgments

The authors are thankful to the Chancellor, Integral University, Lucknow-226026, Uttar Pradesh, India for his sustained encouragement, meticulous supervision, and valuable suggestions at all stages of completion of this chapter. The authors are thankful to the Faculty of Pharmacy, Integral University for providing all the necessary facilities related to the present work. The authors are also thankful for the research cell, Integral University.

Conflict of interest

The authors declare no conflict of interest.