Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells.
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 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.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
Yang
Y
Li
Qing
Q
Zhang
Ruiyang
R
Tian
Qi
Q
Wang
Jean J
JJ
Zhao
J Dirk
JD
Iglehart
Zhigang Charles
ZC
Wang
Andrea L
AL
Richardson
D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D034622:RNA Interference; D013312:Stress, Physiological; D014183:Transplantation, Heterologous
C477083:LAPTM4B protein, human; D008565:Membrane Proteins; D015513:Oncogene Proteins; D002403:Cathepsins