Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells

Yang Li, Qing Zhang, Ruiyang Tian, Qi Wang, Jean J. Zhao, J. Dirk Iglehart, Zhigang Charles Wang, Andrea L. Richardson

Research output: Contribution to journalArticle

53 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)7481-7489
Number of pages9
JournalCancer Research
Volume71
Issue number24
DOIs
StatePublished - Dec 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, Y., Zhang, Q., Tian, R., Wang, Q., Zhao, J. J., Iglehart, J. D., Wang, Z. C., & Richardson, A. L. (2011). Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells. Cancer Research, 71(24), 7481-7489. https://doi.org/10.1158/0008-5472.CAN-11-0940