BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells

Oncotarget
Maria GoulielmakiAlexander Pintzas

Abstract

Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer-both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong...Continue Reading

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Citations

Apr 20, 2018·Cancer·Angelique V OnoratiRavi K Amaravadi
Jan 5, 2017·Molecular Carcinogenesis·Mahamat BabaganaEugene S Kandel
Mar 29, 2019·Anti-cancer Drugs·Masao NishiyaChihaya Maesawa
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Jul 3, 2021·International Journal of Molecular Sciences·Eva Jiménez-MoraAntonio Chiloeches
Jul 25, 2021·Cancers·Mona Foth, Martin McMahon
Jun 26, 2018·Chemical Reviews·Jessica L CounihanDaniel K Nomura

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Methods Mentioned

BETA
lipidation
PCR
confocal microscopy
transfection

Software Mentioned

SELLECKCHEM
LAS AF
- Quant
Image

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