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426 Malakar et al. | Journal of Clinical and Translational Research 2023; 9(6): 423-432
anabolic reactions. These reactions play pivotal roles in 4. Autophagy
various aspects of cancer, including initiation, progression,
metastasis, cell survival, and the development of resistance Christian De Duve first coined the term “autophagy” in 1963
against anti-tumor therapies [32,33]. Indeed, the complete to describe the process of self-eating that he had discovered
metabolic network undergoes significant reprogramming under while studying lysosomes [40]. Since then, the role of autophagy
the influence of oncogenes and tumor suppressor genes [32]. has been explored in numerous research areas including
This restructuring also encompasses a redefinition of nutrient cancer, diabetes, infectious diseases, and neurodegenerative
flow within metabolic networks during the process of tumor disorders [40]. Autophagy is a multistep catabolic signaling cascade
formation. In recent years, there has been a growing interest that orchestrates cytoplasmic content in a double-membrane
in glucose metabolism of cancer cells, which has now become vesicle and fuses with lysosomes, involved in the degradation of
an integral part of cancer biology [32]. Moreover, both damaged organelles such as mitochondria (mitophagy), lipids,
mTORC1 and mTORC2 complexes play a significant role in and proteins, that maintains cellular homeostasis under normal
the regulation of metabolism [34]. Gene expression profiling of circumstances [40]. Autophagy has a multifaceted role in cancer,
pediatric patients diagnosed with ALL revealed the activation with well-established roles for autophagy in promoting tumor
of genes that promote glycolysis, alongside the downregulation cell survival by providing recycled nutrients and modulating
of genes associated with the tricarboxylic acid cycle [35]. mitochondrial function through mitophagy, or intriguing new
Functional analysis conducted on pediatric patients with ALL roles in tumor cell migration and invasion through control of
demonstrated elevated expression of the glucose transport focal adhesion turnover and secretion of pro-migratory cytokines/
protein and glucose transporter 1 [35]. Furthermore, cell lines chemokines [41]. Conversely, autophagy acts as a tumor
derived from ALL exhibited heightened lactate production and suppressor by preventing malignant transformation in mouse
a notable susceptibility to the glycolysis inhibitor, 2-deoxy- models defective for autophagy [42]. Therefore, autophagy
D-glucose [35]. Mutations in genes that encode transcription has both tumor-suppressive and tumor-promoting effects in
factors responsible for regulating glucose metabolism, such as cancer depending on tumor genetics, host variables, and tumor
PAX5 and IKZF1, have been observed in more than 80% of stage [41,43]. Due to its contradictory effects, autophagy has
cases of pre-B-cell ALL [36]. Notably, the combined utilization been considered a double-edged sword in cancer, challenging
of selinexor and azacitidine exhibited synergistic effects by researchers to further investigate how to modulate autophagy in
targeting XPO1/eIF4E/c-MYC signaling pathways in AML, the context of cancer therapies [43,44]. Autophagy has emerged
offering encouraging preclinical data that suggest its potential as one of the critical molecular mechanisms involved in drug
for future clinical application [21] (Table 2). resistance. Chemotherapeutic agents are well known to induce
In preclinical models of triple-negative breast cancer, autophagy in cancer cells [45]. The P38 stress response pathway
selinexor exhibits notable anti-tumor efficacy [21,37]. Selinexor has also been linked to therapeutic resistance and regulation of
treatment induces distinct alterations in AKT signaling and autophagy [46]. Therefore, autophagy may be exploited as a
the expression of genes associated with metabolism in breast promising strategy for the therapeutic sensitization of cancer
cancer cell lines including BT474 and MCF-7 [38]. Moreover, cell [43,44,47].
the combination of selinexor with tamoxifen resulted in a Selinexor treatment of sensitive AML cell lines resulted in a
marked reduction in AKT signaling, and seahorse metabolic heightened DNA damage response [13]. Conversely, in resistant
profiling revealed a significant shift in the metabolic profile AML cell lines, the administration of selinexor led to the
of breast cancer cells. This transition shifted the cells from activation of increased stress response pathways [13]. Moreover,
an energetic state to a quiescent state [38]. Notably, both the in the context of wild type p53 resistant cell line, selinexor
glycolytic and mitochondrial pathways were concurrently treatment upregulated the autophagy pathway, while in mutant
inhibited, thereby inducing autophagy [38]. In addition, p53-resistant cells, selinexor treatment triggered an enhanced p38
selinexor induces autophagy-dependent apoptosis in gallbladder stress response pathway [13]. It is worth noting that selinexor has
cancer by activating the p53/mTOR pathway, both in vitro been shown to induce autophagy-dependent apoptosis in gastric
and in vivo [22]. Interestingly, the inhibition of the glycolytic cancer [22]. Hence, based on this evidence, we propose that
pathway plays a crucial role in modulating autophagy, exerting selinexor might have the capacity to modulate autophagy in the
a significant impact on the survival of leukemia cells [39]. treatment of childhood ALL (Figure 2B).
Consequently, there exists a potential for selinexor to modulate 5. Alternative Splicing
the glycolytic pathway in ALL. However, the precise effect of
selinexor on cancer glucose metabolism in the context of ALL Alternative splicing is a pivotal mechanism governing the
remains unknown (Figure 1B). The significance of conducting regulation of gene expression [48,49]. It entails the excision
experiments aimed at evaluating the impact of selinexor of introns from messenger RNAs, allowing exons to join
treatment on the expression of PAX5 and IKZF1 cannot be together [48,49]. This process of alternative splicing is widely
overstated. These investigations will provide crucial insights deregulated in various cancers, leading to the emergence of
into the potential effects of selinexor on these genes and their cancer-specific splicing experiences widespread dysregulation
relevance in the context of ALL treatments. across diverse cancers, resulting in the emergence of splicing
DOI: http://dx.doi.org/10.18053/jctres.09.202306.23-00088