CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer

Ali, Azhar; Levantini, Elena; Fhu, Chee Wai; Teo, Jun Ting; Clohessy, John G.; Goggi, Julian L.; Wu, Chan-shuo; Chen, Leilei; Chin, Tan Min; Tenen, Daniel G

doi:10.7150/thno.35805

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Theranostics 2019; 9(21):6157-6174. doi:10.7150/thno.35805 This issue Cite

Research Paper

CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer

Azhar Ali^1,#,✉, Elena Levantini^2,3,4,#, Chee Wai Fhu¹, Jun Ting Teo¹, John G. Clohessy^3,7, Julian L. Goggi⁵, Chan-shuo Wu¹, Leilei Chen¹, Tan Min Chin^1,6,*,✉, Daniel G Tenen^1,2,*,✉

1. Cancer Science Institute Singapore, National University of Singapore, MD6, #12-01, 14 Medical Drive, Singapore 117599.
2. Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA
3. Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
4. Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy
5. Singapore Bioimaging Consortium (A*STAR), Helios, 02-02, 11 Biopolis Way, 138667 Singapore
6. Gleneagles Hospital, 6A Napier Road, Singapore 258500
7. Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Cancer Center, Boston, MA 02115, USA
# co-first authors
* co-last authors

Citation:

Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu Cs, Chen L, Chin TM, Tenen DG. CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Theranostics 2019; 9(21):6157-6174. doi:10.7150/thno.35805. https://www.thno.org/v09p6157.htm

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Abstract

Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC.

Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models.

Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions.

Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.

Keywords: Statin, Cav1, glucose uptake, GLUT3, EGFR-TKI resistance, non-small cell lung cancer

Citation styles

APA

Ali, A., Levantini, E., Fhu, C.W., Teo, J.T., Clohessy, J.G., Goggi, J.L., Wu, C.s., Chen, L., Chin, T.M., Tenen, D.G. (2019). CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Theranostics, 9(21), 6157-6174. https://doi.org/10.7150/thno.35805.

ACS

Ali, A.; Levantini, E.; Fhu, C.W.; Teo, J.T.; Clohessy, J.G.; Goggi, J.L.; Wu, C.s.; Chen, L.; Chin, T.M.; Tenen, D.G. CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Theranostics 2019, 9 (21), 6157-6174. DOI: 10.7150/thno.35805.

NLM

CSE

Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu Cs, Chen L, Chin TM, Tenen DG. 2019. CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Theranostics. 9(21):6157-6174.

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