The role of pharmacologic modulation of autophagy on anal cancer development in an HPV mouse model of carcinogenesis

Abstract

Autophagy is an intracellular, catabolic process that maintains cellular health. We examined the response of pharmacologic modulation of autophagy in an HPV mouse model of anal carcinogenesis. K14E6/E7 mice were treated with the topical carcinogen DMBA weekly and assessed for tumors over 20 weeks. Concurrently, they were given either chloroquine or BEZ235, to inhibit or induce autophagy, respectively. Time to tumor onset was examined. Immunofluorescence (IF) was performed for LC3β and p62 to examine autophagy. All DMBA treated K14E6/E7 mice developed anal cancer, contrary to zero of the no DMBA treated mice. Chloroquine plus DMBA resulted in a significant decrease in the time to tumor onset compared to K14E6/E7 treated with DMBA. Only 40% BEZ235 plus DMBA treated mice developed anal cancer. Autophagic induction with DMBA and BEZ235, and autophagic inhibition with chloroquine were confirmed via IF. Anal carcinogenesis can be inhibited or induced via pharmacologic modulation of autophagy.

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Over the past few decades, basal autophagy was reported to remove misfolded proteins and damaged organelles to maintain cellular quality and health, involved in many physical processes of cells such as cellular turnover, differentiation and development (9)(10)(11). Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15).…”

Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development

“…Furthermore, the comparison between HPV16 transgenic mice (K14E6/E7) and non-transgenic mice (FVB/N) display an increased susceptibility to chemical carcinogen, 7,12dimethylbenz[a]anthracene (DMBA) in HPV16 animals, which correlate with an inhibition of autophagosome maturation (Carchman et al, 2016). In line with this, the occurrence of anal tumors induced by DMBA in mice is increased both by the chemical and genetic inhibition of autophagy (Rademacher et al, 2017(Rademacher et al, , 2018. To this regard, Carchman et al (2016) argue that autophagy impairment is mainly associated in early anal cancer development caused by HPV (low-grade dysplasia).…”

Human Papilloma Virus and Autophagy

“…This peculiar pattern of autophagic markers expression, indicating autophagy inhibition at late stages, was also found in human samples, confirming that autophagic dysregulation is a key determinant of HPV-associated anal carcinogenesis [ 39 ]. In support of this hypothesis, treatment of both WT and K14-E6/E7 mice with the late autophagic inhibitor chloroquine significantly increases anal cancer development [ 39 , 40 ], while autophagy activation reduces tumor onset [ 40 ].…”