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Cells
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The Role of Cell Signaling Pathway Starvation Therapy for Cancer
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The Role of Cell Signaling Pathway Starvation Therapy for Cancer

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 1079

Special Issue Editors

Prof. Dr. Niramol Savaraj

E-Mail Website
Guest Editor
Miller School of Medicine, University of Miami, Miami, FL, USA
Interests: cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Min You

E-Mail Website
Guest Editor
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
Interests: tumor necrosis factor

Special Issue Information

Dear Colleagues,

This Special Issue explores cell signaling pathways in starvation therapy, a strategy targeting the oncogenic signaling networks (e.g., PI3K-AKT-mTOR, HIF, and c-Myc) that drive cancer's metabolic reprogramming. Tumors rewire pathways governing nutrient uptake (glucose, amino acids, and lipids) and utilization to fuel growth. Starvation therapy aims to disrupt these signals, cutting off the tumor's nutrient supply.

Key approaches include inhibiting glucose transporters/kinases, restricting serine/glycine availability, and blocking glutamine metabolism or lipogenic enzymes. Critically, these interventions not only directly starve cancer cells but also reshape the tumor microenvironment. They can activate immunostimulatory pathways, modulate immune checkpoint expression, and overcome immunosuppression. Advanced delivery systems enhance specificity.

While promising, challenges remain, such as tumor heterogeneity, compensatory metabolic pathways, systemic toxicity, and the identification of predictive biomarkers. Future success hinges on optimizing combinatorial strategies, integrating starvation therapy effectively with immunotherapy, targeted agents, and nanotechnology for precise clinical translation.

This Special Issue will offer reviews and original research on cell signaling pathways in starvation therapy in cells and animal model studies.

Prof. Dr. Niramol Savaraj
Dr. Min You
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • signaling pathways
  • nutrient deprivation
  • starvation therapy
  • metabolic reprogramming
  • metabolic pathways

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Published Papers (2 papers)

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Research

20 pages, 2336 KB  
Article
Loss of PIK3CA Allows In Vitro Growth but Not In Vivo Progression of KRAS Mutant Lung Adenocarcinoma in a Syngeneic Orthotopic Implantation Model
by Abigail L. Booth, Giuseppe Caso, Barbara Rosati, Ya-Ping Jiang, Wei-Xing Zong, Richard Z. Lin and Harold Bien
Cells 2026, 15(6), 506; https://doi.org/10.3390/cells15060506 - 12 Mar 2026
Viewed by 291
Abstract
Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in [...] Read more.
Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in mouse models with an intact Trp53 tumor suppressor. In this study, we further investigated the requirement of PIK3CA for tumor growth both in vitro and in vivo. We first generated a “KPA” cell line by genetically deleting Pik3ca from a murine lung adenocarcinoma “KP” cell line harboring oncogenic KrasG12D and lacking Trp53. We also examined the requirement for STK11, a tumor suppressor and metabolic regulator frequently co-mutated with KRAS in lung cancer. We found that Pik3ca is not required for cell survival and growth in vitro, even under anchorage-independent conditions, but reduced the growth rate by 15%. We next orthotopically implanted KP and KPA cells into syngeneic mice and found that PIK3CA is absolutely required for tumor progression, even in the absence of Trp53. Implantation of KP cells, or a “KPS” cell line lacking the Stk11 gene, led to rapid tumor growth and death of all host animals. In contrast, mice implanted with KPA cells all survived with no detectable lung tumors. The gene expression profiles from cultured cell lines suggest oxidative stress as a potential vulnerability of KPA cells. Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results indicate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS in vitro but is essential for in vivo progression and growth. Full article
(This article belongs to the Special Issue The Role of Cell Signaling Pathway Starvation Therapy for Cancer)
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19 pages, 2620 KB  
Article
WWOX Induction Promotes Bcl-XL and Mcl-1 Degradation Through a Lysosomal Pathway upon Stress Responses
by Yu-Han Su, Wei Chiang, Yi-Yu Wang, Yi-Hsi Kung, Pai-Shan Cheng, Tsung-Hao Chang, Nan-Shan Chang, Feng-Jie Lai and Li-Jin Hsu
Cells 2026, 15(3), 270; https://doi.org/10.3390/cells15030270 - 31 Jan 2026
Viewed by 513
Abstract
The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We [...] Read more.
The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We demonstrated that stress responses, including serum deprivation, oxidative stress, and anticancer drug treatment, increase WWOX expression in human SCC-15 cells and wild-type mouse embryonic fibroblasts (MEFs) through transcriptional activation. Serum deprivation induces higher levels of reactive oxygen species and cell death in Wwox+/+ than Wwox−/− MEFs. Anti-apoptotic Bcl-2 family proteins regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that serum starvation decreases protein expression levels of Bcl-XL and Mcl-1 in Wwox+/+ but not in Wwox−/− MEFs. Serum starvation also fails to downregulate Bcl-XL and Mcl-1 protein expression in WWOX-knockdown SCC-15 cells. Replenishment of ectopic WWOX induces downregulation of Bcl-XL and Mcl-1 protein levels in Wwox−/− MEFs after serum starvation. We determined that WWOX-mediated downregulation of Bcl-XL and Mcl-1 is accomplished through a lysosome-dependent protein degradation pathway. Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death. Full article
(This article belongs to the Special Issue The Role of Cell Signaling Pathway Starvation Therapy for Cancer)
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