Autophagy inhibition by TSSC4 (tumor suppressing subtransferable candidate 4) contributes to sustainable cancer cell growth

ABSTRACT

Cancer cell growth is dependent upon the sustainability of proliferative signaling and resisting cell death. Macroautophagy/autophagy promotes cancer cell growth by providing nutrients to cells and preventing cell death. This is in contrast to autophagy promoting cell death under some conditions. The mechanism regulating autophagy-mediated cancer cell growth remains unclear. Herein, we demonstrate that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor that suppresses cancer cell growth and tumor growth and prevents cell death induction during excessive growth by inhibiting autophagy. The oncogenic proteins ERBB2 (erb-b2 receptor tyrosine kinase 2) and the activation EGFR mutant (EGFRvIII, epidermal growth factor receptor variant III) promote cell growth and TSSC4 expression in breast cancer and glioblastoma multiforme (GBM) cells, respectively. In EGFRvIII-expressing GBM cells, TSSC4 knockout shifted the function of autophagy from a pro-cell survival role to a pro-cell death role during prolonged cell growth. Furthermore, the interaction of TSSC4 with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via its conserved LC3-interacting region (LIR) contributes to its inhibition of autophagy. Finally, TSSC4 suppresses tumorsphere formation and tumor growth by inhibiting autophagy and maintaining cell survival in tumorspheres. Taken together, sustainable cancer cell growth can be achieved by autophagy inhibition via TSSC4 expression.

Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; CQ: chloroquine; EGFRvIII: epidermal growth factor receptor variant III; ERBB2: erb-b2 receptor tyrosine kinase 2; GBM: glioblastoma multiforme; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule Associated protein 1 light chain 3; TSSC4: tumor suppressing subtransferable candidate 4

KEYWORDS:

• Autophagic cell death
• cell growth
• EGFR
• ERBB2
• tumorsphere

Acknowledgments

We thank Manitoba Tumor Bank supported by the CancerCare Manitoba Foundation for performing the sectioning of tumor tissues and Andrea Fristensky for her help in sectioning the paraffin-embedded tumor tissues. We would like to thank Dr. Shujun Huang for her help in bioinformatics, Dr. Afshin Raouf for providing the MCF10A cell line, Dr. D Neil Watkins for reading the manuscript. This work was supported by a grant from CancerCare Manitoba Foundation and the NATURAL SCIENCES AND ENGINEERING RESEARCH COUNCIL of Canada (NSERC) awarded to S.B.G.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary materials

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the CancerCare Manitoba Foundation [761063311].