Biology subjects

Achanta, K.

Publications and source records attributed to Achanta, K..

3 recordsLinked to original sources

bioRxiv2025

Androgen receptor contributes to radioresistance through DNA repair and autophagy in AR-positive prostate cancer cells

Androgen receptor (AR) is a critical therapeutic target in prostate cancer (PCa), and androgen blockade is known to act synergistically with radiation therapy. However, the mechanisms through which AR modulates radiation response are not yet fully understood. In this study, we aimed to investigate the role of AR in mediating radioresistance in PCa. AR-positive LNCaP and castration-resistant C4-2 cells exhibited significantly higher radioresistance than AR-negative cells, as determined by apoptosis and cell viability assays. Following irradiation, most LNCaP cells were arrested in the G1 phase, accompanied by rapid p53 activation and p21 induction. Consistently, AR silencing significantly increased radiosensitivity and reduced DNA-PKcs expression and phosphorylation, suggesting that AR enhances DNA repair, likely through non-homologous end joining (NHEJ). At the cellular level, irradiation markedly induced macroautophagy in LNCaP and C4-2 cells, as evidenced by increased LC3B-II accumulation and autophagic vacuole formation, and the upregulation of 11 autophagy-related genes was identified by whole-transcriptomic analysis. To assess their functional relevance, we performed siRNA-mediated knockdown of selected autophagy-related genes and assessed cell viability and Annexin V/PI staining. Notably, BECN1 and LC3 knockdown significantly enhanced radiosensitivity, with BECN1 knockdown showing an effect comparable to that observed with AR silencing. These results suggest that radiation-induced autophagy promotes the survival of AR-positive prostate cancer cells. Moreover, immunohistochemical analysis of ex vivo-irradiated, patient-derived PCa tissues from patients with newly diagnosed high-Gleason score prostate cancer undergoing prostatectomy further demonstrated that radiation-induced autophagy supports the survival of high-grade AR-positive tumor cells. Collectively, our findings reveal that AR promotes radioresistance in PCa by enhancing both DNA repair and autophagy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/690226v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@3f713corg.highwire.dtl.DTLVardef@1233a11org.highwire.dtl.DTLVardef@1b94e5eorg.highwire.dtl.DTLVardef@c8338c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer lacking effective drugs and therefore new treatment targets are needed. Transcriptomic analysis comparing human embryonic and PDAC tissue identified a large overlap of expression profiles suggesting a re-initiation of developmental programs in pancreatic cancer. Specifically, we identified the transcription factors HOXB6 and HOXB8 as potential key regulators in PDAC. Loss of HOXB6 and HOXB8 in pancreatic cancer cells inhibited cell proliferation, induced apoptosis and senescence and enhanced gemcitabine sensitivity. Moreover, reduced HOXB6 and HOXB8 expression in pancreatic and lung adenocarcinoma cell lines affected transcription of immune response pathways which resulted in an increased sensitivity of cancer cells to anti-tumorigenic activities of macrophages suggesting that the HOXB6 and HOXB8 immune regulatory pattern is conserved in different cancer types. Additionally, naive M0 macrophages exposed to HOXB8 deficient PDAC cells were unable to differentiate into tumor associated macrophages, suggesting that HOXB8 promotes the transition of initial anti-tumor macrophage to a tumor-promoting macrophage phenotype in pancreatic cancer. Our findings indicate that HOXB6 and HOXB8 play important roles in regulating cell proliferation, immune response and treatment resistance to promote pancreatic cancer tumorigenesis and could be useful therapeutic targets.

cancer biology↗

bioRxiv2024

The interplay between dormant mutated cells and tumor promotion by chronic tissue damage in determining cancer risk.

While the causal role of mutagenic carcinogens in tumor development is well established, the relative contribution of environmental tumor promoting factors, wounding, and chronic inflammation is still unclear. Recent sequencing studies have suggested that most environmental carcinogens act as promoters rather than through mechanisms that involve direct induction of point mutations, but whether cancer risk factors such as obesity, chronic inflammation, wounding, or tumor promoters contribute directly or indirectly to mutation burden, or induce novel signatures, has not been investigated. Here, we present WGS analysis of over 100 mouse skin tumors to compare the effects of exposure to mutagens, the tumor promoter TPA, chronic wounding, obesity, or chemotherapy, on mutational burden and cancer risk. All tumors initiated by the carcinogen Dimethylbenzanthracene (DMBA) show a very strong A>T mutational signature (SBS.DMBA) attributable to a single exposure to this carcinogen. The number of SBS.DMBA mutations also showed a strong correlation with the "clock" signature SBS5, suggesting that one treatment with this mutagen can induce mutational signatures attributed to endogenous processes. No specific signatures could be attributed to obesity, high fat diet, wounding, or TPA. Cells carrying thousands of mutations persist over very long periods without inducing tumors or causing pathological changes but can give rise to tumors after short term exposure to TPA. Furthermore, normal cell turnover and proliferation during fetal and adult growth, is not sufficient for promotion, but tissue damage followed by regenerative proliferation seems to be required for tumor development. We conclude that tumor promoters, chronic inflammation, wounding, and obesity do not contribute significantly to tumor mutational burden, and that the rate-limiting determinant of tumor growth is exposure to a tumor promoter rather than the nature or number of genomic point mutations. These data are highly relevant to the recent demonstration of persistent oncogenic mutations in histologically normal human tissues during ageing.

cancer biology↗