TFEB confers resistance against the chemotherapeutic agent CX-5461

Identifying mechanisms underlying chemoresistance is essential for improving the efficacy of chemotherapeutic drugs. Previously, we showed that cancer cells respond to gemcitabine by activating protective signals dependent on the master regulator of autophagy and lysosomal biogenesis, transcription factor EB (TFEB). However, how gemcitabine triggers these protective responses remains elusive. While gemcitabine primarily aims at disrupting DNA replication, it is also suspected to induce nucleolar stress. In this study, we aimed to examine the effect of gemcitabine on nucleolar stress and investigate whether nucleolar stress inducers could trigger TFEB-dependent protective signals. Besides gemcitabine causing nucleolar stress, the anticancer agent CX-5461, primarily designed to induce nucleolar stress, promoted TFEB nuclear accumulation. Interfering with TFEB improved the sensitivity of cancer cells to both CX-5461 and gemcitabine. Our findings suggest that TFEB provides broad protection against the stress caused by chemotherapeutic drugs, representing a promising target for intercepting chemoresistance and improving the efficacy of anticancer agents.