Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

Abstract

Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD⁺ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.

Keywords: ERK5; NAD+; cardiovascular diseases; p90RSK; senescence-associated secretory phenotype (SASP).

Figure 1.

NAD⁺ metabolism in cells and its compartmentalization^[99,103]. Human cells produce NAD⁺ through three major pathways: the Kynurenine pathway, Preiss-Handler pathway, and Salvage pathway. In the Kynurenine pathway, which is a de novo pathway, the precursor molecule, tryptophan (Trp), after entering the cells via the transporters SLC7A5 and SLC36A4, is converted to N-formyl kynurenine (FK) by the rate-limiting enzyme indoleamine 2,3- dioxygenase (IDO) or the rate-limiting enzyme tryptophan 2,3- dioxygenase (TDO) and then FK is converted to kynurenine. The kynurenine aminotransferases (KATs) convert kynurenine to kynurenic acid, further converted to quinaldic acid. In addition to this, kynurenine 3-monooxygenase (KMO) converts kynurenine to 3- hydroxykynurenine (3-HK), which is further transformed to 3- hydroxy anthranilic acid (3-HAA) by tryptophan 2,3- dioxygenase (KYNU). The 3-HAA gives rise to α- amino- β- carboxy muconate ε- semialdehyde (ACMS) by the enzyme 3-hydroxyanthranilic acid oxygenase (3HAO). Finally, ACMS is transformed to picolinic acid by α-amino-β-carboxy muconate-ε-semialdehyde decarboxylase (ACMSD) or quinolinic acid. In the Preiss-Handler pathway, the precursor molecule nicotinic acid (NA) first enters the cells via SLC5A8 or SLC22A3 transporters. It is then converted to nicotinic acid mononucleotide (NAMN) by the enzyme nicotinic acid phosphoribosyltransferase (NAPRT), which is then converted into nicotinic acid adenine dinucleotide (NAAD) by the enzymes called nicotinamide mononucleotide adenylyl transferases (NMNAT1, NMNAT2, and NMNAT3). Next, NAD⁺ synthase (NADS) transforms NAAD to NAD⁺. The NAD⁺ can be directly phosphorylated by NAD⁺ kinase (NADK) to produce NADP(H). In the Salvage pathway, the intracellular nicotinamide (NAM) is recycled back to NAD⁺ via the formation of nicotinamide mononucleotide (NMN) by intracellular nicotinamide phosphoribosyltransferase (iNAMPT). The NAM is the byproduct generated by the NAD⁺ consuming enzymes, sirtuins, poly (ADP-ribose) polymerases (PARPs), CD38, CD157, and SARM1. The Salvage pathway also uses nicotinamide riboside (NR) to produce the NMN via the enzyme nicotinamide riboside kinases 1 and 2 (NRK1 and NRK2). The cellular NAD⁺ level is balanced by biosynthesis and consumption in different subcellular compartments. For example, in the cytoplasm, the intracellular NAMPT (iNAMPT) converts NAM to NMN, further transformed to NAD⁺ by another cytoplasm-specific enzyme, NMNAT2. The NADH, generated from the NAD⁺ in the cytoplasm and utilized by Glycolysis, is transported to the mitochondria via the malate/aspartate shuttle. Via the electron transport chain (ETC), the NADH is oxidized to NAD⁺ by mitochondria specific complex I, while by tricarboxylic acid (TCA) cycle, the NAD⁺ is transformed to NADH. The mitochondrial SIRT 3, 4, 5 convert NAD⁺ to NAM. The NADH can enter the mitochondria via the glyceraldehyde 3- phosphate shuttle and results in reduced flavin adenine dinucleotide (FADH2), which is converted to the FADH mitochondrial complex II. The mitochondrial transporter SLC25A51 can also help the direct mitochondrial entry of NAD ⁺. The nuclear NAD⁺ pool equilibrates with the cytosolic NAD⁺ pool by diffusion through the unidentified nuclear pore^[99,103]. The nuclear enzymes SIRT 1, 6, 7, and PARPs, CD38, SARM1, consume NAD⁺ and regulate the NAD⁺ homeostasis in the nucleus.

Figure 2.

The SASP is sustained by a positive feedback loop constituted by p90RSK-ERK5 S496^[77]. In the cells exposed to chemoradiation, a sustained SASP is maintained for the long term via the positive feedback loop. (1) The chemoradiation induces the production of mitochondrial ROS (mtROS) in the mitochondria, which in turn (2) increases the p90RSK phosphorylation leading to ERK5 S496 phosphorylation, the decreased transcriptional activity of ERK5, and reduced NRF2 transcriptional activity. Consequently, the (3) level of cellular antioxidant is dropped, causing (4) telomeric DNA damage, (5) PARP activation, and leading to NAD⁺ depletion. (6) The NAD⁺ depletion causes mitochondrial dysfunction, along with severe ATP depletion, termed reversible mitochondrial (mt) stunning, which further (7) causes mtROS production and reactivates the same p90RSK-ERK5-NRF2 module, thus constituting a positive feedback loop. This figure was modified from the figure in reference^[77]