Inhibition of chaperone‑mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer

Abstract

Chaperone-mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines. In engineered 5-FU-resistant CRC cell lines, a significant elevation of lysosome-associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5-FU resistance and to enhance PLD2 expression through the activation of NF-κB pathway. Accordingly, loss or gain of function of LAMP2A in 5-FU-resistant CRC cells rendered them sensitive or resistant to 5-FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5-FU treatment and anti-CMA therapy may be a novel therapeutic option for patients with CRC.

Chaperone-Mediated Autophagy and Its Implications for Neurodegeneration and Cancer

“…The result showed that CMA is a promising predictor of chemosensitivity to 5‑FU treatment and anti‑CMA therapy may be a novel therapeutic option for patients with colorectal cancer. 41 A similar study was also done and showed that inhibiting CMA activity in breast tumor cells can be exploited as a potential therapeutic application in the treatment of breast cancer. 49 Considering the physiological anti-oncogenic role of CMA, there is general agreement that preventive interventions should aim at restoring CMA activity to that in healthy conditions.…”

“… 3 CMA is activated in a variety of cancers, including breast, colorectal, gastric, and liver cancer, indicating that LAMP2A overexpression promotes tumor growth and metastasis. 41 CMA up-regulation may play a role in cancer pathology development. CMA’s role in promoting cancer cell survival has been linked to several mechanisms, including preventing cells from entering an apoptotic state, providing general protection against oxidative stress, and protecting pro-oncogenic proteins from degradation by other pathways.…”

“… 42 Inhibition of chaperone mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer. 41 Moreover, CMA degrades the multifunctional protein HSD17B4, which modulates the properties for the invasion and migration of cells. 20 In addition, inhibition of CMA in lung cancer cells markedly decreased their metastatic potential by reducing migration and resistance to anoikis (a form of programmed cell death that occurs in tumor cells when they were detached from the surrounding extracellular matrix).…”

The Emerging Role of EVA1A in Different Types of Cancers

“…EVA1A promoted oxaliplatin resistance of HCC by inducing autophagy [ 52 ]. Autophagy has been reported to promote cancer drug resistance [ 53 ], and also the strengthened drug sensitivity of cancer [ 54 ]. The above self-contradictory report may be related to the type of cancer or drug.…”

Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy

“…For a protein to be selectively degraded via the CMA pathway, it needs to have the pentapeptide motif of KFERQ in its protein sequence [382]. CMA has been shown to participate in both physiological and pathological situations, including the cell cycle, maintaining hematopoietic stem-cell function, aging, neurodegenerative diseases, and cancers [383][384][385][386][387][388][389]. CMA is also regulated at different levels, from cell membrane proteins to chaperone proteins in the cytoplasm, through Lamp2a, Hsc70, GFAP, EF1α, and the mTORC2/PHLPP1/Akt signaling axis [390][391][392].…”