Claudin-1 Helps Prostate Cancer Survive Chemotherapy by Easing Cellular Stress

Prostate cancer has a notorious ability to change its identity when doctors push it hard with treatment. When androgen deprivation therapy and modern androgen receptor pathway inhibitors strip tumors of the hormonal fuel they depend on, a subset of cancer cells responds not by dying but by transforming. They shed their glandular lineage and reprogram themselves into a neuroendocrine-like state, a shift known as neuroendocrine transdifferentiation. The resulting tumors, classified as neuroendocrine prostate cancer, are among the most lethal forms of castration-resistant disease, and they routinely shrug off docetaxel, one of the mainstay chemotherapy drugs for advanced prostate cancer. A new study published in Cellular and Molecular Life Sciences now reveals an unexpected molecular mechanism behind this deadly metamorphosis, and it centers on a protein that scientists thought they already understood.

Claudin-1, or CLDN1, has long been defined by its day job. It is a tight junction protein, a structural component that seals the gaps between epithelial cells, controlling what passes through tissue barriers and holding cellular sheets together. In cancer research, CLDN1 has mostly been studied in that architectural context, with its dysregulation implicated in tumor progression and metastasis across multiple cancer types. But the new work, led by researchers at Nanjing Medical University and collaborating institutions in China, demonstrates that CLDN1 has a second, hidden life inside the cell. Far from the cell membrane’s junctions, the protein operates deep within the endoplasmic reticulum, the organelle responsible for folding and quality-controlling the proteins that cells need to survive.

The endoplasmic reticulum is an unforgiving workplace. When protein folding demands exceed the organelle’s capacity, misfolded proteins accumulate and trigger a condition called endoplasmic reticulum stress. If the stress is mild, the cell activates adaptive signaling pathways that expand folding capacity and restore balance. If the stress is severe or prolonged, the same machinery flips into a destructive mode, executing a form of programmed cell death designed to eliminate damaged cells. Chemotherapy drugs such as docetaxel impose exactly this kind of burden, overwhelming the folding machinery and pushing cancer cells toward the lethal threshold. The researchers reasoned that tumors which survive this assault must have found ways to buffer the stress, and their search for those buffers led them directly to CLDN1.

To identify the key regulators of neuroendocrine differentiation and docetaxel resistance, the team integrated transcriptome data from multiple public cohorts with their own RNA sequencing of prostate cancer models. This multi-cohort analysis pinpointed CLDN1 as a consistent feature of both neuroendocrine prostate cancer and chemotherapy-resistant tumors. The correlation was striking: in clinical tissue specimens from human prostate cancer patients, CLDN1 expression showed a significant positive relationship with established neuroendocrine markers such as neuron-specific enolase and synaptophysin. In other words, the tumors that expressed the most CLDN1 were the ones most likely to display the neuroendocrine signature that portends aggressive, treatment-resistant disease.

Having established the clinical association, the researchers moved into mechanistic territory. Using co-immunoprecipitation coupled with mass spectrometry, they mapped the proteins that physically associate with CLDN1 and discovered that it interacts with two critical players in endoplasmic reticulum biology. The first is USP7, a deubiquitinase enzyme that removes ubiquitin tags from target proteins. Ubiquitin attachment is the cell’s universal signal for destruction, so deubiquitinases act as molecular rescuers, pulling proteins back from the degradation pathway. The second player is calnexin, or CANX, a chaperone protein embedded in the endoplasmic reticulum membrane that helps newly synthesized proteins fold correctly and directs misfolded ones toward degradation.

The experiments revealed a precise biochemical sequence. CLDN1 promotes the recruitment of USP7 to the endoplasmic reticulum membrane, where USP7 removes ubiquitin molecules from calnexin at three specific conserved lysine residues, numbered K118, K170, and K199. The team confirmed this site specificity through ubiquitination assays and site-directed mutagenesis, showing that altering these lysines abolished the protective effect. With its ubiquitin tags removed, calnexin is stabilized, and the endoplasmic reticulum gains a larger and more durable folding workforce. Transmission electron microscopy provided visual confirmation of the cellular consequences, revealing that CLDN1-high cells maintained endoplasmic reticulum structure under conditions that would otherwise damage the organelle. The practical result is that chemotherapy-induced stress, which should push these cells over the lethal threshold, is instead absorbed and neutralized.

The functional consequences of this buffering system extend beyond simple survival. Using gain- and loss-of-function approaches in prostate cancer cell lines, the researchers showed that CLDN1 drives neuroendocrine transdifferentiation, pushing cells toward the lineage-plastic state that characterizes treatment-resistant disease. Conversely, depleting CLDN1 undermined both the neuroendocrine shift and resistance to docetaxel. The team validated these findings in vivo using subcutaneous xenograft models in mice, where manipulating CLDN1 levels changed how tumors responded to chemotherapy. The picture that emerges is of a single protein coordinating two of the most feared features of advanced prostate cancer: the identity change that escapes targeted therapies and the stress tolerance that escapes cytotoxic drugs.

Perhaps the most therapeutically exciting finding came when the researchers deliberately reversed the process. Tunicamycin, a pharmacological agent that blocks a key step in protein glycosylation and thereby activates endoplasmic reticulum stress, effectively reversed CLDN1-induced neuroendocrine differentiation and chemoresistance in the animal models. In essence, re-imposing the stress that CLDN1 had learned to buffer stripped the tumors of their adaptive advantage. This proof-of-concept experiment suggests that the endoplasmic reticulum stress response is not merely a bystander in treatment resistance but an actionable vulnerability. If clinicians could pharmacologically tip the stress balance in the lethal direction at the right moment, they might prevent or reverse the lineage plasticity that makes neuroendocrine prostate cancer so difficult to treat.

The study also expands the conceptual framework of cancer biology in a broader sense. Tight junction proteins have traditionally been studied as structural elements, and organelle homeostasis has traditionally been studied through dedicated stress-response pathways. The CLDN1-USP7-CANX axis demonstrates that these worlds intersect, with a junctional protein moonlighting as a regulator of deubiquitinase recruitment and chaperone stability deep inside the cell. This noncanonical function provides a molecular link between cell architecture, protein quality control, and tumor cell reprogramming, and it raises the question of whether other tight junction proteins harbor similar hidden roles in organelle biology. The finding also adds to a growing appreciation that post-translational modifications, particularly site-specific deubiquitination, can serve as master switches controlling how cancer cells respond to therapeutic pressure.

For patients with advanced prostate cancer, the clinical stakes are considerable. Neuroendocrine prostate cancer typically emerges after years of androgen receptor-targeted treatment, and once it appears, prognosis is poor because neither hormonal manipulation nor standard chemotherapy works reliably. The identification of the CLDN1-USP7-CANX pathway offers several potential intervention points: blocking the CLDN1-USP7 interaction, inhibiting USP7 recruitment to the endoplasmic reticulum, or pharmacologically exploiting the stress vulnerability that CLDN1 normally shields. USP7 inhibitors already exist in early clinical development for other indications, which could accelerate translational efforts. The work was supported by the National Natural Science Foundation of China and the Jiangsu Provincial Health Commission, and the corresponding authors include Lei Yang, Haoli Yin, and Qingyi Zhu. While the road from mechanism to medicine is long, this study provides a clear molecular target for a disease state that has stubbornly resisted every previous attempt at rational attack, and it demonstrates that sometimes the most important discoveries about a well-known protein are found in the places no one thought to look.

Subject of Research: The role of Claudin-1 in endoplasmic reticulum stress regulation, lineage plasticity, and chemoresistance in prostate cancer

Article Title: Noncanonical function of Claudin-1 mitigates lethal endoplasmic reticulum stress to drive prostate cancer lineage plasticity and chemoresistance

Article References: Li, Y., Li, Y., Li, S., Li, K., Dong, Y., Chen, Z., Zhou, K., Ji, Z., Yang, L., Yin, H., & Zhu, Q. (2026). Noncanonical function of Claudin-1 mitigates lethal endoplasmic reticulum stress to drive prostate cancer lineage plasticity and chemoresistance. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06430-8

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06430-8

Keywords: prostate cancer, Claudin-1, neuroendocrine prostate cancer, endoplasmic reticulum stress, lineage plasticity, chemoresistance, docetaxel, USP7, calnexin, deubiquitination, castration-resistant prostate cancer, tumor reprogramming