Liver Cancer’s Stem Cell Traits and Drug Resistance Driven by p38β

A key protein and its mechanism of action that drive stem cell traits and resistance in liver cancer that does not respond to cancer drugs have been identified.

A research team led by Professor Tang Min at The Chinese University of Hong Kong identified a key mechanism by which the stress-activated enzyme p38β (MAPK11) drives resistance in hepatocellular carcinoma (HCC), the international journal Nature Communications reported on the 5th.

According to the study, p38β phosphorylates a specific site on the endoplasmic reticulum (ER) molecular chaperone BiP protein (threonine 648). This process promotes stronger binding of BiP to the unfolded protein response (UPR) sensors PERK and IRE1-α.

As a result, activation of the UPR, the cancer cells’ stress response, is suppressed. This allows cancer cells to maintain protein homeostasis and survive under stressful conditions such as chemotherapy, while retaining their traits as tumor-initiating cells (TICs) and their drug resistance.

In patients with HCC, higher p38β expression was associated with a poorer prognosis and disease progression.

The research team targeted this mechanism using HA15, a BiP inhibitor. The suppressed UPR signaling was restored, and sensitivity to the cancer drug cisplatin increased again in patient-derived xenograft (PDX) and organoid models.

This study is the first to show that the p38β-BiP axis is a key factor regulating homeostasis in tumor-initiating cells. It is significant because it identifies a new therapeutic target for HCC, which is difficult to treat.