Lysosomal Transmembrane Protein LAPTM4B Promotes Autophagy and Tolerance to Metabolic Stress in Cancer Cells

Abstract

Amplification of chromosome 8q22, which includes the gene for lysosomal-associated transmembrane protein LAPTM4B, has been linked to de novo anthracycline resistance in primary breast cancers with poor prognosis. LAPTM4B overexpression can induce cytosolic retention of anthracyclines and to decrease drug induced DNA damage. In this study, we tested the hypothesis that LAPTM4B may contribute to tumor cell growth or survival in the absence of a chemotherapeutic exposure. In mammary cells, LAPTM4B protein was localized in lysosomes where its depletion increased membrane permeability, pH, cathepsin release and cellular apoptosis. Loss of LAPTM4B also inhibited later stages of autophagy by blocking maturation of the autophagosome, thereby rendering cells more sensitive to nutrient deprivation or hypoxia. Conversely, enforced overexpression of LAPTM4B promoted autophagic flux and cell survival during in vitro starvation and stimulated more rapid tumor growth in vivo. Together, our results indicate that LAPTM4B is required for lysosome homeostasis, acidification, and function, and that LAPTM4B renders tumor cells resistant to lysosome-mediated cell death triggered by environmental and genotoxic stresses.

LAPTM5 Protein Is a Positive Regulator of Proinflammatory Signaling Pathways in Macrophages

“…Although several studies have implicated the ubiquitously expressed LAPTM4 proteins in mediating drug resistance, as well as function in autophagy, the role of the immune cell specific LAPTM5 has been less clear (27)(28)(29). In this study, we present evidence that LAPTM5 acts as a positive regulator of multiple inflammatory signaling cascades in macrophages.…”

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

“…3D, showing a sharp increase in nuclear doxorubicin starting at roughly 2 Â 10 5 HER2 per cell. High HER2 expression was necessary, but not sufficient, for efficient nuclear delivery of doxorubicin, possibly reflecting the activity of drug efflux transporters or other sequestration mechanisms (42). A parallel experiment A B C D Figure 2.…”

Emerging roles of PtdIns(4,5)P2 – beyond the plasma membrane

“…Future studies are, thus, needed to identify the specific PIPKs and any additional PtdIns(4,5)P 2 effectors that are involved in this step of autophagy. Of note, recent studies have shown a role for the endosomally localized LAPTM4B, a PIPKIγi5-interacting protein, in both autophagy initiation and maturation (Li et al, 2011;Tan et al, 2015b). Given the dynamic nature of ER-endosome contacts (Friedman et al, 2013), it would be interesting to investigate whether the PIPKIγi5-mediated PtdIns(4,5)P 2 signaling is involved in autophagy regulation by regulating these interactions.…”